Novel sulfonyl derivatives

ABSTRACT

Described in the present invention are a sulfonyl derivative represented by the following formula (I):  
     Q 1 -Q 2 -T 1 -Q 3 -SO 2 -Q A   (I)  
     [wherein Q 1  represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group, 5- or 6-membered heterocyclic group, dicyclic fused ring or tricyclic fused ring group which may have a substituent;  
     Q 2  represents a single bond, an oxygen atom, a sulfur atom, a linear or branched C 1-6  alkylene group or the like;  
     Q A  represents an arylalkenyl group which may have a substituent or a heteroarylalkenyl group which may have a substituent; and  
     T 1  represents a carbonyl group or the like] and a medicament comprising the same. The compound has strong FXa inhibitory action, provides prompt, sufficient and long-lasting anti-thrombus effects when orally administered, and has low side effects and is therefore useful as an excellent anticoagulant.

TECHNICAL FIELD

[0001] The present invention relates to a novel, orally-administrablesulfonyl derivative or salt thereof which inhibits an activatedcoagulation factor X (which will hereinafter be abbreviated as “FXa”),thereby exhibiting strong anticoagulant action; and a coagulationsuppressor or preventive and/or remedy for thrombosis or embolism whichcomprises the derivative or salt as an effective ingredient.

BACKGROUND ART

[0002] Exasperation of coagulation activity is an important factor forunstable angina, cerebral infarction, cerebral embolism, myocardialinfarction, pulmonary infarction, pulmonary embolism, Buerger's disease,deep vein thrombosis, disseminated intravascular coagulation syndrome,thrombus formation after valve replacement, reocclusion afterrevascularization or formation of thrombus upon extracorporealcirculation. There is accordingly a demand for an excellentanticoagulant which is excellent in dose-responsiveness, haslong-lasting effects, has a low risk of hemorrhage, has less sideeffects and exhibits rapid and sufficient effects even by oraladministration (Thrombosis Research, 68, 507-512, 1992).

[0003] Studies on anticoagulants based on various acting mechanismssuggest that a FXa inhibitor has a possibility of becoming an excellentanticoagulant. The coagulation system is a series of reactions wherein alarge amount of a thrombus is produced through an amplification step dueto a multi-stage enzymatic reaction and induces the formation ofinsoluble fibrin. In the intrinsic system, after the multi-stagereaction following the activation of a contact factor, activated FactorIX activates factor X on a phospholipid membrane in the presence ofactivated Factor VIII and a calcium ion, while in the extrinsic system,activated Factor VII activates Factor X in the presence of a tissuefactor. In other words, the activation of Factor X into FXa in thecoagulation system is an essential reaction in the formation ofthrombin. Activated Factor X (FXa) in each system carries out limitedproteolysis of prothrombin, thereby forming thrombin. The resultingthrombin activates the coagulation factors on the upstream side, wherebythe formation of thrombin is amplified further. As described above, thecoagulation system upstream of FXa is separated into intrinsic andextrinsic systems so that the inhibition of the enzyme of thecoagulation system upstream of FXa does not suppress the production ofFXa sufficiently, inevitably resulting in the production of thrombin.Furthermore, the coagulation occurs as a self-amplifying reaction sothat the suppression of the coagulation system can be accomplished moreefficiently by the inhibition of FXa which exists upstream of thethrombin than by the inhibition of the thrombin formed (ThrombosisResearch, 15, 617629(1979)).

[0004] Another merit of the FXa inhibitor is that an effective dose in athrombus model is largely different from the dose for extending thebleeding time in an experimental hemorrhage model. From the experimentalresult, the FXa inhibitor is presumed to be an anticoagulant with a lowrisk of hemorrhage.

[0005] As a FXa inhibitor, various compounds are reported. In general,antithrombin III or antithrombin III-dependent penta-saccharide is knownto have no inhibitory action against a prothrombinase complex whichplays a practical role in the thrombus formation in vivo (ThrombosisResearch, 68, 507-512-(1992); Journal of Clinical Investigation, 71,1383-1389(1983); Mebio, August issue, 92-97) and moreover, it does notexhibit effectiveness in oral administration. Although tickanticoagulant peptide (TAP) (Science, 248, 593-596(1990)) or antistacin(AST) (Journal of Biological Chemistry, 263, 10162-10167(1988)) isolatedfrom a tick or leech which is a bloodsucker inhibits FXa and exhibitsanti-thrombus effects on the models of from venous thrombus to arterialthrombus, it is not effective when orally administered because it is ahigh-molecular peptide. From such a viewpoint, a low-molecular FXainhibitor which directly inhibits a coagulation factor without dependingon antithrombin III has been developed.

[0006] An object of the present invention is to provide, as an excellentanticoagulant, a novel sulfonyl derivative or salt thereof, or a solvatethereof which has strong FXa inhibitory action, exhibits prompt,sufficient and long-lasting anti-thrombus effects even by the oraladministration and has less side effects.

DISCLOSURE OF THE INVENTION

[0007] With the forgoing in view, the present inventors have carried outan extensive investigation on the synthesis of a novel FXa inhibitor andits pharmacological action. As a result, it has been found that a novelsulfonyl derivative or salt thereof, or solvate thereof exhibits strongFXa inhibitory activity and strong anticoagulant activity, inhibits FXastrongly, promptly and continuously by the oral administration, exhibitsanti-coagulant action and anti-thrombus action, is highly safe and isuseful as a preventive or remedy for various diseases caused by athrombus embolus.

[0008] The present invention relates to a sulfonyl derivativerepresented by the below-described formula (I) or salt thereof, or asolvate thereof: Chemical formula (I):

Q¹-Q²-T¹-Q³-SO₂-Q^(A)  (I)

[0009] [wherein, Q¹ represents a saturated or unsaturated 5- or6-membered cyclic hydrocarbon group which may have a substituent, asaturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent, a saturated or unsaturated dicyclic fused ring groupwhich may have a substituent or a saturated or unsaturated tricyclicfused ring group which may have a substituent;

[0010] Q² represents a single bond, an oxygen atom, a sulfur atom, alinear or branched C₁₋₆ alkylene group, a linear or branched C₂₋₆alkenylene group, a linear or branched C₂₋₆ alkynylene group,

[0011] a group —N-(R¹)—CO—

[0012] (in which R¹ represents a hydrogen atom or an alkyl group),

[0013] a group —N-(R²)(CH₂)_(m)—

[0014] (in which R² represents a hydrogen atom or an alkyl group and mstands for an integer of 0 to 6), or

[0015] a group of the following formula:

[0016] (which represents a divalent, saturated or unsaturated 5 or6-membered cyclic hydrocarbon group which may have a substituent, adivalent, saturated or unsaturated 5- or 6-membered heterocyclic groupwhich may have a substituent or a divalent, saturated or unsaturateddicyclic fused ring group which may have a substituent and ←C means thebonding of the carbon atom of this group to Q¹),

[0017] Q³ represents any one of the following groups:

[0018] (in which when the carbon atom to which each of R³, R⁴, R⁵, R⁶,R⁷, R⁸, R¹⁰ and R¹¹ has been bonded is not adjacent to a nitrogen atom,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ each independently represents ahydrogen atom,

[0019] a hydroxyl group,

[0020] an alkyl group,

[0021] an alkoxyl group,

[0022] an alkoxyalkyl group,

[0023] an alkoxyalkyloxy group,

[0024] a hydroxyalkyl group,

[0025] a hydroxyalkyloxy group,

[0026] a hydroxyalkylcarbonyl group,

[0027] a hydroxyalkylsulfonyl group,

[0028] a formyl group,

[0029] a formylalkyl group,

[0030] a formylalkylcarbonyl group,

[0031] a formylalkylsulfonyl group,

[0032] an alkylcarbonyl group,

[0033] an alkylsulfonyl group,

[0034] an alkylcarbonylalkyl group,

[0035] an alkylsulfonylalkyl group,

[0036] a carboxyl group,

[0037] a carboxyalkyl group,

[0038] a carboxyalkyloxy group,

[0039] a carboxyalkylcarbonyl group,

[0040] a carboxyalkylsulfonyl group,

[0041] a carboxyalkylcarbonylalkyl group,

[0042] a carboxyalkylsulfonylalkyl group,

[0043] an alkoxycarbonyl group,

[0044] an alkoxycarbonylalkyl group,

[0045] an alkoxycarbonylalkyloxy group,

[0046] an alkoxycarbonylalkylcarbonyl group,

[0047] an alkoxycarbonylalkylsulfonyl group,

[0048] an amino group which may have one or two substituents,

[0049] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents,

[0050] an aminoalkyloxy group which may have, at the amino moietythereof, one or two substituents,

[0051] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0052] an aminoalkylcarbonyloxy group which may have, at the aminomoiety thereof, one or two substituents,

[0053] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0054] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0055] an aminocarbonylalkyloxy group which may have, at the aminomoiety thereof, one or two substituents,

[0056] an alkylsulfonylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent,

[0057] an arylsulfonylaminocarbonyl group which may have, at the aminomoiety thereof, one substituent,

[0058] an aminosulfonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0059] a cyanoalkyl group,

[0060] an alkoxyalkylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent,

[0061] an alkylcarbonyloxyalkyl group, or

[0062] a group A¹-B¹— (in which A¹ represents a saturated or unsaturated5- or 6-membered cyclic hydrocarbon group which may have a substituentor a saturated or unsaturated 5- or 6-membered heterocyclic group whichmay have a substituent and B¹ represents a single bond, a carbonylgroup, an alkylene group, a carbonylalkyl group, a group —O—(C₁₋₆alkylene), a group —COO—(C₁₋₆ alkylene), a group —NHCO— or a group—NHCO—(C₁₋₆ alkylene),

[0063] when the carbon atom to which each of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰and R¹¹ has been bonded is adjacent to a nitrogen atom, R³, R⁴, R⁵, R⁶,R⁷, R⁸, R¹⁰ and R¹¹ each independently represents

[0064] a hydrogen atom,

[0065] an alkyl group,

[0066] a hydroxyalkyl group,

[0067] a hydroxyalkylcarbonyl group,

[0068] a hydroxyalkylsulfonyl group,

[0069] a formyl group,

[0070] a formylalkyl group,

[0071] a formylalkylcarbonyl group,

[0072] a formylalkylsulfonyl group,

[0073] an alkylcarbonyl group,

[0074] an alkylsulfonyl group,

[0075] an alkylcarbonylalkyl group,

[0076] an alkylsulfonylalkyl group,

[0077] a carboxyl group,

[0078] a carboxyalkyl group,

[0079] a carboxyalkylcarbonyl group,

[0080] a carboxyalkylsulfonyl group,

[0081] a carboxyalkylcarbonylalkyl group,

[0082] a carboxyalkylsulfonylalkyl group,

[0083] an alkoxyalkyl group,

[0084] an alkoxycarbonyl group,

[0085] an alkoxycarbonylalkyl group,

[0086] an alkoxycarbonylalkylcarbonyl group,

[0087] an alkoxycarbonylalkylsulfonyl group,

[0088] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents,

[0089] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0090] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0091] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents

[0092] an alkylsulfonylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent,

[0093] an arylsulfonylaminocarbonyl group which may have, at the aminomoiety thereof, one substituent,

[0094] an aminosulfonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0095] a cyanoalkyl group,

[0096] an alkoxyalkylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent,

[0097] an alkylcarbonyloxyalkyl, or

[0098] a group A²-B²— (in which A² represents a saturated or unsaturated5- or 6-membered cyclic hydrocarbon group which may have a substituentor a saturated or unsaturated 5- or 6-membered heterocyclic group whichmay have a substituent, and B² represents a single bond, a carbonylgroup, an alkylene group, a carbonylalkyl group, a group —O—(C₁₋₆alkylene), a group —COO—(C₁₋₆ alkylene), a group —NHCO— or a group—NHCO—(C₁₋₆ alkylene group),

[0099] each of R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, and R¹⁰ and R¹¹ may becoupled together with a carbon atom which constitutes the ring andrepresent a saturated or unsaturated 5- to 7-membered cyclic hydrocarbongroup which may have a substituent or a saturated or unsaturated 5- to7-membered heterocyclic group which may have a substituent, R⁹ and R¹²each independently represents:

[0100] a hydrogen atom,

[0101] an alkyl group,

[0102] a hydroxyalkyl group,

[0103] a hydroxyalkylcarbonyl group,

[0104] a hydroxyalkylsulfonyl group,

[0105] an alkoxyl group,

[0106] an alkoxyalkyl group,

[0107] an alkoxyalkylcarbonyl group,

[0108] an alkoxyalkylsulfonyl group,

[0109] a formyl group,

[0110] a formylalkyl group,

[0111] a formylalkylcarbonyl group,

[0112] a formylalkylsulfonyl group,

[0113] an alkylcarbonyl group,

[0114] an alkylcarbonylalkyl group,

[0115] an alkylsulfonyl group,

[0116] an alkylsulfonylalkyl group,

[0117] a carboxyalkyl group,

[0118] a carboxyalkylcarbonyl group,

[0119] a carboxyalkylsulfonyl group,

[0120] a carboxyalkylcarbonylalkyl group,

[0121] a carboxyalkylsulfonylalkyl group,

[0122] an alkoxycarbonyl group,

[0123] an alkoxycarbonylalkyl group,

[0124] an alkoxycarbonylalkylcarbonyl group,

[0125] an alkoxycarbonylalkylsulfonyl group,

[0126] an amino group which may have one or two substituents,

[0127] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents

[0128] an aminoalkyloxy group which may have, at the amino moietythereof, one or two substituents,

[0129] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0130] an aminoalkyloxycarbonyl group which may have, at the aminomoiety thereof, one or two substituents,

[0131] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0132] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0133] an aminocarbonyloxyalkyl group which may have, at the aminomoiety thereof, one or two substituents,

[0134] an alkylsulfonylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent,

[0135] an arylsulfonylaminocarbonyl group which may have, at the aminomoiety thereof, one substituent,

[0136] an aminosulfonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0137] a cyanoalkyl group,

[0138] an alkoxyalkylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent, or

[0139] an alkylcarbonyloxyalkyl,

[0140] R⁹ and R⁷ or R⁸ may be coupled together with a carbon atomconstituting the ring and a nitrogen atom to which R⁹ has been bondedand represent a saturated or unsaturated 5- to 7-membered heterocyclicgroup which may have a substituent,

[0141] R¹² and R¹⁰ or R¹¹ may be coupled together with a carbon atomconstituting the ring and a nitrogen atom to which R¹² has been bondedand represent a saturated or unsaturated 5 to 7-membered heterocyclicgroup which may have a substituent,

[0142] a, b, d, e and g each independently stands for an integer of 0 or1, c stands for an integer of 0 to 3, and f, h and i each independentlyrepresents an integer of 1 to 3, with the proviso that the sum of a, band c stands for an integer of 2 or 3, the sum of d and e stands for aninteger of 0 or 1 and the sum of f, g and h stands for an integer of 3to 5),

[0143] Q^(A) represents an arylalkenyl group which may have asubstituent, a heteroarylalkenyl group which may have a substituent, asaturated or unsaturated dicyclic fused ring group which may have asubstituent, a saturated or unsaturated tricyclic fused ring group whichmay have a substituent, a group Ar—C(H)═N— (in which, Ar represents anaryl group which may have a substituent), or a group Het-C(H)═N— (inwhich, Het represents a heteroaryl group which may have a substituent),and

[0144] T¹ represents a carbonyl group,

[0145] a group —CH(R¹³)—

[0146] (in which R¹³ represents a hydrogen atom, an alkyl group, ahydroxyalkyl group having the hydroxyl group which may be protected, analkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group,an aryl group, an aralkyl group,

[0147] a heteroaryl group, a heteroarylalkyl group or an aminoalkylgroup which may have, at the amino moiety thereof, a substituent(protecting group)), or

[0148] a group —C(═NOR¹⁴)— or —C(═N—NHR^(14′))—

[0149] (in which R¹⁴ and R^(14′) each independently represents ahydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonylgroup, an aryl group, an aralkyl group, a heteroaryl group, aheteroarylalkyl group or an aminoalkyl group which may have, at theamino moiety thereof, a substituent.

[0150] The present invention also provides a pharmaceutical comprisingas an effective ingredient a sulfonyl derivative represented by theabove-described formula (I) or salt thereof, or a solvate thereof.

[0151] The present invention also provides a pharmaceutical compositioncomprising a sulfonyl derivative represented by the above-describedformula (I) or salt thereof, or a solvate thereof and a pharmaceuticallyacceptable carrier.

[0152] The present invention also provides use of a sulfonyl derivativerepresented by the above-described formula (I) or salt thereof, or asolvate thereof as a pharmaceutical.

[0153] The present invention also provides a method for treatingdiseases caused by FXa, blood coagulating diseases and various diseasesdue to thrombosis or embolism, which comprises administering a sulfonylderivative represented by the above-described formula (I) or saltthereof, or a solvate thereof.

BEST MODES FOR CARRYING OUT THE INVENTION

[0154] A description will next be made of the substituents in thesulfonyl group derivative of the formula (I) according to the presentinvention.

[0155] <About Group Q^(A)>

[0156] Q^(A) represents an arylalkenyl group which may have asubstituent, a heteroarylalkenyl group which may have a substituent, asaturated or unsaturated dicyclic fused ring group which may have asubstituent, a saturated or unsaturated tricyclic fused ring group whichmay have a substituent, a group Ar—C(H)═N— (in which, Ar represents anaryl group which may have a substituent), or a group Het-C(H)═N— (inwhich, Het represents a heteroaryl group which may have a substituent).

[0157] In the group Q^(A), the term “arylalkenyl group which may have asubstituent” means a group composed of an aryl group and a linear,branched or cyclic C₂₋₆ alkenylene group. Examples of the aryl groupinclude phenyl, naphthyl, anthryl and phenanthryl group. Examples of thearylalkenyl group include phenylethenyl group.

[0158] The “heteroarylalkenyl group which may have a substituent” meansa group composed of a heteroaryl group and a linear, branched or cyclicC₂₋₆ alkenylene group. The “heteroaryl group” means an aromaticmonovalent group having at least one hetero atom and examples includepyridyl, furyl and thienyl groups. Examples of the heteroarylalkenylgroup include pyridylethenyl group.

[0159] The “saturated or unsaturated, dicyclic or tricyclic fused ringgroup which may have a substituent” means: 1) a group obtained by thecondensation of saturated or unsaturated 5- or 6-membered cyclichydrocarbon groups which may have a substituent, 2) a group obtained bythe condensation of a saturated or unsaturated 5- or 6-membered cyclichydrocarbon group which may have a substituent and a saturated orunsaturated 5- or 6-membered heterocyclic group which may have asubstituent and 3) a group obtained by the condensation of saturated orunsaturated 5- or 6-membered heterocyclic groups which may have asubstituent.

[0160] Examples of the saturated or unsaturated 5- or 6-membered cyclichydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl,cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl groups. When thegroup has plural structural isomers as the cyclopentenyl group, they areall embraced in it.

[0161] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinyl.Where the group has plural structural isomers as the pyranyl, it is tobe noted that they are all embraced in it.

[0162] Examples of the group 1) include indenyl, indanyl, naphthyl,tetrahydronaphthyl, anthryl and phenanthryl; those of the group 2)include benzofuranyl, benzothienyl, indolyl, indolinyl, quinolyl,benzodiazinyl, tetrahydroisoquinolyl, benzothiazolyl,tetrahydrobenzothiazolyl and isoindolyl; and those of the group 3)include naphthyridinyl, tetrahydrothienopyridyl,tetrahydrothiazolopyridyl, tetrahydropyridopyridyl, thiazolopyridazinyl,tetrahydrothiazolopyridazinyl, pyrrolopyridyl, tetrahydropyrrolopyridyl,dihydropyridoquinazolinyl, pyridopyrimidinyl,tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl, andtetrahydrooxazolopyridyl.

[0163] The aryl group in the group Ar—C(H)═N (wherein Ar represents anaryl group which may have a substituent) means an aryl group similar tothat described above. The group Ar—C(CH)═N— means a group composed of aphenyl group which may have a substituent and a group —C(H)═N— or thelike.

[0164] The heteroaryl group in the group Het-C(H)═N— (wherein Hetrepresents a heteroaryl group which may have a substituent) means aheteroaryl group similar to that described above. The group Het-C(H)═N—means a group composed of a pyridyl group which may have a substituentand a group Het-C(H)═N—.

[0165] Each of the arylalkenyl group, heteroarylalkenyl group, saturatedor unsaturated dicylic fused ring group, saturated or unsaturatedtricyclic fused ring group, the group Ar—C(H)═N— and the groupHet-C(H)═N— may have one or two substituents. Examples of thesubstituent include a hydroxyl group, halogen atoms such as fluorine,chlorine, bromine and iodine, halogenomethyl groups having 1 to 3halogen atoms substituted, an amino group, a cyano group, an aminomethylgroup, an amidino group, a hydroxyamidino group, linear, branched orcyclic C₁₋₆ alkyl groups (ex. methyl and ethyl), linear, branched orcyclic C₁₋₆ alkoxyl groups (ex. methoxyl and ethoxyl), linear, branchedor cyclic C₂₋₇ alkoxycarbonylamidino groups (ex. methoxycarbonylamidinoand ethoxycarbonylamidino), linear, branched or cyclic C₂₋₆ alkenylgroups (ex. vinyl and allyl), linear, branched or cyclic C₂₋₆ alkynylgroups (ex. ethynyl and propynyl), linear, branched or cyclic C₂₋₆alkoxycarbonyl groups (ex. methoxycarbonyl and ethoxycarbonyl) andaminocarbonyl groups.

[0166] More specifically, the group Q^(A) represents any one of thefollowing groups.

[0167] A description will next be made of the substituent in thesegroups.

[0168] In the group

[0169] R¹⁵ represents a hydrogen atom, a hydroxyl group, a nitro group,a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, analkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkylgroup, an alkylcarbonyl group, an alkoxycarbonyl group, analkoxycarbonyalkyl group, an alkylcarbonyloxy group or a group A³-B³(wherein, A³ represents an amino group which may have one or twosubstituents, a saturated or unsaturated 5- or 6-membered cyclichydrocarbon group which may have a substituent or a saturated orunsaturated 5- or 6-membered heterocyclic group which may have asubstituent and B³ represents a single bond, a carbonyl group, analkylene group, a carbonylalkyl group, a carbonylalkyloxy group or analkylenecarbonyloxy group).

[0170] In R¹⁵, examples of the halogen atom include fluorine, chlorine,bromine and iodine.

[0171] Examples of the alkyl group include linear, branched or cyclicC₁₋₆ alkyl groups such as methyl, ethyl, isopropyl and cyclopropyl.

[0172] The “hydroxyalkyl group” means a group composed of a hydroxylgroup and a linear, branched or cyclic C₁₋₆ alkylene group. Examples ofthe alkylene group include methylene, ethylene, trimethylene, propyleneand cyclohexylene. Examples of the hydroxyalkyl group includehydroxymethyl and hydroxyethyl.

[0173] The “alkoxyl group” means a group formed of the above-describedC₁₋₆ alkyl group and an oxygen atom. Examples include methoxyl, ethoxyland isopropoxyl.

[0174] The “alkoxyalkyl group” means a group formed of a linear,branched or cyclic C₁₋₆ alkoxyl group and a linear, branched or cyclicC₁₋₆ alkylene group. Examples include methoxymethyl, methoxyethyl andethoxymethyl.

[0175] The “carboxyalkyl group” means a group formed of a carboxyl groupand a linear, branched or cyclic C₁₋₆ alkylene group. Examples includecarboxymethyl and carboxyethyl.

[0176] The “alkylcarbonyl group” means a group formed of a linear,branched or cyclic C₁₋₆ alkyl group and a carbonyl group. Examplesinclude methylcarbonyl and ethylcarbonyl.

[0177] The “alkoxycarbonyl group” means a group formed of a linear,branched or cyclic alkoxyl group and a carbonyl group. Examples includemethoxycarbonyl and ethoxycarbonyl.

[0178] The “alkoxycarbonylalkyl group” means a group formed of a linear,branched or cyclic C₂₋₇ alkoxycarbonyl group and a linear, branched orcyclic C₁₋₆ alkylene group. Examples include methoxycarbonylethyl andethoxycarbonylmethyl.

[0179] The “alkylcarbonyloxy group” means a group formed of a linear,branched or cyclic C₂₋₇ alkylcarbonyl group and an oxygen atom. Examplesinclude methylcarbonyloxy, ethylcarbonyloxy and isopropylcarbonyloxy.

[0180] In the group A³-B³—, A³ means an amino group which may have oneor two substituents, a saturated or unsaturated 5 or 6-membered cyclichydrocarbon group which may have a substituent or a saturated orunsaturated 5- or 6-membered heterocyclic group which may have asubstituent.

[0181] When A³ means an amino group which may have one or twosubstituents, B³ represents a single bond, a carbonyl group, an alkylenegroup, a carbonylalkyl group, a carbonylalkyloxy group or analkylenecarbonyloxy group. The group A³-B³— therefore means, forexample, a group as shown in the following class (A).

[0182] Class (A):

[0183] an amino group which may have one or two substituents,

[0184] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0185] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents,

[0186] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0187] an aminocarbonylalkyloxy group which may have, at the aminomoiety thereof, one or two substituents,

[0188] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents and

[0189] an aminoalkylcarbonyloxy group which may have, at the aminomoiety thereof, one or two substituents.

[0190] A description will next be made of the groups shown in Class (A).

[0191] The “aminocarbonyl group which may have, at the amino moietythereof, one or two substituents” means a group formed of an amino groupwhich may have one or two substituents and a carbonyl group.

[0192] The “aminoalkyl group which may have, at the amino moietythereof, one or two substituents” means a group formed of an amino groupwhich may have one or two substituents and a linear, branched or cyclicC₁₋₆ alkylene group. Examples of the aminoalkyl group includeaminomethyl and aminoethyl.

[0193] The “aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents” means a group formed of theabove-described aminocarbonyl group and a linear, branched or cyclicC₁₋₆ alkylene group. Examples of the aminocarbonylalkyl group includeaminocarbonylmethyl and aminocarbonylethyl.

[0194] The “aminocarbonylalkyloxy group which may have, at the aminomoiety, one or two substituents” means a group formed of theabove-described aminocarbonylakyl group which may have a substituent andan oxygen atom. Examples of the aminocarbonylalkyloxy group includeaminocarbonylmethoxyl and aminocarbonylethoxyl.

[0195] The “aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents” means a group formed of theabove-described aminoalkyl group which may have a substituent and acarbonyl group. Examples of the aminoalkylcarbonyl group includeaminomethylcarbonyl and aminoethylcarbonyl.

[0196] The “aminoalkylcarbonyloxy group which may have, at the aminomoiety thereof, one or two substituents” means a group formed of theabove-described aminoalkylcarbonyl group which may have a substituentand an oxygen atom. Examples of the aminoalkylcarbonyloxy group includeaminomethylcarbonyloxy and aminoethylcarbonyloxy.

[0197] Examples of the substituent which can be substituted for an aminogroup (moiety) include those as shown in the following Class (1).

[0198] Class (1):

[0199] an alkyl group,

[0200] an alkenyl group,

[0201] a halogenoalkyl group,

[0202] a halogenoalkenyl group,

[0203] a hydroxyalkyl group,

[0204] a hyroxyalkylcarbonyl group,

[0205] a hydroxyalkylsulfonyl group,

[0206] an alkoxyl group,

[0207] an alkoxyalkyl group,

[0208] an alkoxyalkylcarbonyl group,

[0209] an alkoxyalkylsulfonyl group,

[0210] a formyl group,

[0211] a formylalkyl group,

[0212] a formylalkylcarbonyl group,

[0213] a formylalkylsulfonyl group,

[0214] an alkylcarbonyl group,

[0215] an alkylcarbonylalkyl group,

[0216] an alkylsulfonyl group,

[0217] an alkylsulfonylalkyl group,

[0218] a carboxyalkyl group,

[0219] a carboxyalkylcarbonyl group,

[0220] a carboxyalkylsulfonyl group,

[0221] a carboxyalkylcarbonylalkyl group,

[0222] a carboxyalkylsulfonylalkyl group,

[0223] an alkoxycarbonyl group,

[0224] an alkoxycarbonylalkyl group,

[0225] an alkoxycarbonylalkylcarbonyl group,

[0226] an alkoxycarbonylalkylsulfonyl group,

[0227] a trifluoromethylsulfonyloxyalkenyl group and

[0228] a group a³-b³-

[0229] (wherein a³ represents a saturated or unsaturated 5- or6-membered cyclic hydrocarbon group or saturated or unsaturated 5- or6-membered heterocyclic group which may have one to three substituentsselected from the group consisting of a halogen atom, a hydroxyl group,an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitrogroup, a carboxyl group, an alkoxycarbonyl group and an aminocarbonylgroup; and

[0230] b³ represents a single bond, a carbonyl group, an alkylene group,a carbonylalkyl group, a carbonylalkyloxy group, an alkylenecarbonyloxygroup, an alkyleneaminocarbonyl group, an alkyleneaminocarbonylalkylgroup, an alkyleneaminosulfonyl group or an alkyleneaminosulfonylalkylgroup.

[0231] The substituents which can be substituted for an amino group(moiety) in Class (1) will next be described.

[0232] The “alkyl group” means a linear, branched or cyclic C₁₋₆ alkylgroup.

[0233] The “alkenyl group” means a linear, branched or cyclic C₂₋₆alkenyl group. Examples include vinyl and allyl.

[0234] The “halogenoalkyl group” means a group formed of a halogen atomand a linear, branched or cyclic C₁₋₆ alkylene group. Examples includechloromethyl and bromoethyl.

[0235] The “halogenoalkenyl group” means a group formed of a halogenatom and a linear or branched C₂₋₆ alkenylene group. Examples includechlorovinyl and bromoallyl groups. There is no particular limitation onthe position of a double bond.

[0236] The “hydroxyalkyl group” means a group formed of a hydroxyl groupand a linear, branched or cyclic C₂₋₆ alkylene group. Examples includehydroxyethyl and hydroxypropyl.

[0237] The “hydroxyalkylcarbonyl group” means a group formed of theabove-described hydroxyalkyl group and a carbonyl group. Examplesinclude hydroxymethylcarbonyl and hydroxyethylcarbonyl.

[0238] The “hydroxyalkylsulfonyl group” means a group formed of theabove-described hydroxyalkyl group and a sulfonyl group. Examplesinclude hydroxymethylsulfonyl and hydroxyethylsulfonyl. The “alkoxylgroup” means a linear, branched or cyclic C₁₋₆ alkoxyl group.

[0239] The “alkoxyalkyl group” means a group formed of a linear,branched or cyclic C₁₋₆ alkoxyl group and a linear, branched or cyclicC₂₋₆ alkylene group. Examples include methoxyethyl, ethoxyethyl andmethoxypropyl.

[0240] The “alkoxyalkylcarbonyl group” means a group formed of theabove-described alkoxyalkyl group and a carbonyl group. Examples includemethoxyethylcarbonyl and ethoxymethylcarbonyl.

[0241] The “alkoxyalkylsulfonyl group” means a group formed of theabove-described alkoxyalkyl group and a sulfonyl group. Examples includemethoxyethylsulfonyl and ethoxymethylsulfonyl.

[0242] The “formylalkyl group” means a group formed of a formyl groupand a linear, branched or cyclic C₁₋₆ alkylene group. Examples includeformylmethyl and formylethyl.

[0243] The “formylalkylcarbonyl group” means a group formed of theabove-described formylalkyl group and a carbonyl group. Examples includeformylmethylcarbonyl and formylethylcarbonyl.

[0244] The “formylalkylsulfonyl group” means a group formed of theabove-described formylalkyl group and a sulfonyl group. Examples includeformylmethylsulfonyl and formylethylsulfonyl.

[0245] The “alkylcarbonyl group” means a group formed of a linear,branched or cyclic C₁₋₆ alkyl group and a carbonyl group. Examplesinclude methylcarbonyl and ethylcarbonyl.

[0246] The “alkylcarbonylalkyl group” means a group formed of theabove-described alkylcarbonyl group and a linear, branched or cyclicC₁₋₆ alkylene group. Examples include methylcarbonylmethyl andethylcarbonylmethyl.

[0247] The “alkylsulfonyl group” means a group formed of theabove-described alkyl group and a sulfonyl group. Examples includemethylsulfonyl and ethylsulfonyl.

[0248] The “alkylsulfonylalkyl group” means a group formed of theabove-described alkylsulfonyl group and a linear, branched or cyclicC₁₋₆ alkylene group. Examples include methylsulfonylmethyl andethylsulfonylmethyl.

[0249] The “carboxyalkyl group” means a group composed of a carboxylgroup and a linear, branched or cyclic C₁₋₆ alkylene group.

[0250] The “carboxyalkylcarbonyl group” means a group formed of theabove-described carboxyalkyl group and a carbonyl group. Examplesinclude carboxymethylcarbonyl and carboxyethylcarbonyl.

[0251] The “carboxyalkylsulfonyl group” means a group formed of theabove-described carboxyalkyl group and a sulfonyl group. Examplesinclude carboxymethylsulfonyl and carboxyethylsulfonyl.

[0252] The “carboxyalkylcarbonylalkyl group” means a group formed of theabove-described carboxyalkylcarbonyl group and a linear, branched orcyclic C₁₋₆ alkylene group. Examples include carboxymethylcarbonylmethyland carboxyethylcarbonylmethyl.

[0253] The “carboxyalkylsulfonylalkyl group” means a group formed of theabove-described carboxyalkylsulfonyl group and a linear, branched orcyclic C₁₋₆ alkylene group. Examples include carboxymethylsulfonylmethyland carboxyethylsulfonylmethyl.

[0254] The “alkoxycarbonyl group” means a group formed of a linear,branched or cyclic C₁₋₆ alkoxyl and a carbonyl group.

[0255] The “alkoxycarbonylalkyl group” means a group formed of theabove-described alkoxycarbonyl group and a linear, branched or cyclicC₁₋₆ alkylene group.

[0256] The “alkoxycarbonylalkylcarbonyl group” means a group formed ofthe above-described alkoxycarbonylalkyl group and a carbonyl group.Examples include methoxycarbonylethylcarbonyl andethoxycarbonylmethylcarbonyl.

[0257] The “alkoxycarbonylalkylsulfonyl group” means a group of theabove-described alkoxycarbonylalkyl group and a sulfonyl group. Examplesinclude methoxycarbonylethylsulfonyl and ethoxycarbonylmethylsulfonyl.

[0258] The “trifluoromethylsulfonyloxyalkenyl group” means a groupformed of a trifluoromethylsulfonyloxy group and a linear or branchedC₂₋₆ alkenylene group. Examples include trifluoromethylsulfonyloxyvinyland trifluoromethylsulfonyloxyallyl.

[0259] In the group a³-b³-, a³ represents a saturated or unsaturated 5-or 6-membered cyclic hydrocarbon group or saturated or unsaturated 5- or6-membered heterocyclic group which may have a substituent such as ahalogen atom. Examples of the saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group include cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.Where the group has, as the cyclopentenyl, plural structural isomers,they are all embraced in it.

[0260] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinyl.Where the group has, as the pyranyl, plural structural isomers, they areall embraced in it.

[0261] b³ represents a single bond or a divalent group such as carbonyl,alkylene, carbonylalkyl, carbonylalkyloxy, alkylenecarbonyloxy,alkyleneaminocarbonyl, alkyleneaminocarbonylalkyl, alkyleneaminosulfonylor alkyleneaminosulfonylalkyl. The “alkylene group” means a linear,branched or cyclic C₁₋₆ alkylene group.

[0262] The “carbonylalkyl group” means a group formed of a carbonylgroup and a linear, branched or cyclic C₁₋₆ alkylene group. Examplesinclude carbonylmethyl and carbonylethyl.

[0263] The “carbonylalkyloxy group” means a group formed of theabove-described carbonylalkyl group and an oxygen atom. Examples includecarbonylmethoxy and carbonylethoxy.

[0264] The “alkylenecarbonyloxy group” means a group formed of a linear,branched or cyclic C₁₋₆ alkylene group, a carbonyl group and an oxygenatom. Examples include methylenecarbonyloxy and ethylenecarbonyloxy.

[0265] The “alkyleneaminocarbonyl group” means a group formed of alinear, branched or cyclic C₁₋₆ alkylene group, an imino group and acarbonyl group. Examples include methyleneaminocarbonyl andethyleneaminocarbonyl.

[0266] The “alkyleneaminocarbonylalkyl group” means a group formed ofthe above-described alkyleneaminocarbonyl and a linear, branched orcyclic C₁₋₆ alkylene. Examples include methyleneaminocarbonylmethyl andethyleneaminocarbonylmethyl.

[0267] The “alkyleneaminosulfonyl group” means a group formed of alinear, branched or cyclic C₁₋₆ alkylene group, an imino group and asulfonyl group. Examples include methyleneaminosulfonyl andethyleneaminosulfonyl.

[0268] The “alkyleneaminosulfonylalkyl group” means a group formed ofthe above-described alkyleneaminosulfonyl and a linear, branched orcyclic C₁₋₆ alkylene group. Examples includemethyleneaminosulfonylmethyl and ethyleneaminosulfonylmethyl.

[0269] A description will next be made of the substituents which can beintroduced into, as the above-described a³, a saturated or unsaturated5- or 6-membered cyclic hydrocarbon group or saturated or unsaturated 5-or 6-membered heterocyclic group. Examples include halogen atoms, analkoxyl group, an alkyl group, an alkoxycarbonyl and an aminocarbonylgroup.

[0270] As the group a³-b³-, there exist various kinds according to thecombination of a³ and b³. Examples include:

[0271] a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbongroup which may have a substituent,

[0272] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and a carbonyl group,

[0273] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent and an alkylenegroup,

[0274] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and a carbonylalkylgroup,

[0275] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent and acarbonylalkyloxy group,

[0276] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and aalkylenecarbonyloxy group,

[0277] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent and analkyleneaminocarbonyl group,

[0278] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and analkyleneaminocarbonylalkyl group,

[0279] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent and analkyleneaminosulfonyl group,

[0280] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and analkyleneaminosulfonylalkyl group, and the like.

[0281] In addition to the above-described Class (1), the following Class(2) can be given as examples of the substituent which can be substitutedfor the amino group (moiety).

[0282] Class (2):

[0283] an amino group which may have one or two substituents selectedfrom Class (1),

[0284] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents selected from Class (1),

[0285] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents selected from Class (1),

[0286] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents selected from Class (1),

[0287] an aminocarbonylalkylcarbonyl group which may have, at the aminomoiety thereof, one or two substituents selected from Class (1),

[0288] an aminocarbonylalkylsulfonyl group which may have, at the aminomoiety thereof, one or two substituents selected from Class (1),

[0289] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents selected from Class (1),

[0290] an aminosulfonyl group which may have, at the amino moietythereof, one or two substituents selected from Class (1),

[0291] an aminosulfonylalkyl group which may have, at the amino moietythereof, one or two substituents selected from Class (1),

[0292] an aminoalkylsulfonyl group which may have, at the amino moietythereof, one or two substituents selected from Class (1),

[0293] an aminosulfonylalkylcarbonyl group which may have, at the aminomoiety thereof, one or two substituents selected from Class (1) and

[0294] an aminosulfonylalkylsulfonyl group which may have, at the aminomoiety thereof, one or two substituents selected from Class (1).

[0295] A description will next be made of the substituents of Class (2).

[0296] The aminoalkyl, aminocarbonyl, aminocarbonylalkyl andaminoalkylcarbonyl groups in Class (2) have the same meanings asdescribed above.

[0297] The “aminoalkyl group which may have a substituent at the aminomoiety” means a group formed of an amino group which may have theabove-described substituent and a linear, branched or cyclic C₂₋₆alkylene group. Examples of the aminoalkyl group include aminoethyl andaminopropyl.

[0298] The “aminocarbonylalkylcarbonyl group which may have asubstituent at the amino moiety” means a group formed of anaminocarbonylalkyl group which may have the above-described substituentand a carbonyl group. Examples of the aminocarbonylalkylcarbonyl groupinclude aminocarbonylmethylcarbonyl and aminocarbonylethylcarbonyl.

[0299] The “aminocarbonylalkylsulfonyl group which may have, at theamino moiety thereof, a substituent” means a group formed of anaminocarbonylalkyl group which may have the above-described substituentand a sulfonyl group. Examples of the aminocarbonylalkylsulfonyl groupinclude aminocarbonylmethylsulfonyl and aminocarbonylethylsulfonyl.

[0300] The “aminosulfonyl group which may have, at the amino moietythereof, a substituent” means a group formed of an amino group which mayhave the above-described substituent and a sulfonyl group.

[0301] The “aminosulfonylalkyl group which may have, at the amino moietythereof, a substituent” means a group formed of an aminosulfonyl groupwhich may have the above-described substituent and a linear, branched orcyclic C₁₋₆ alkylene group. Examples of the aminosulfonylalkyl groupinclude aminosulfonylmethyl and aminosulfonylethyl.

[0302] The “aminoalkylsulfonyl group which may have, at the amino moietythereof, a substituent” means a group formed of an aminoalkyl groupwhich may have the above-described substituent and a sulfonyl group.Examples of the aminoalkylsulfonyl group include aminomethylsulfonyl andaminoethylsulfonyl.

[0303] The “aminosulfonylalkylcarbonyl group which may have, at theamino moiety thereof, a substituent” means a group formed of anaminosulfonylalkyl group which may have the above-described substituentand a carbonyl group. Examples of the aminosulfonylalkylcarbonyl groupinclude aminosulfonylmethylcarbonyl and aminosulfonylethylcarbonyl.

[0304] The “aminosulfonylalkylsulfonyl group which may have, at theamino moiety thereof, a substituent” means a group formed of anaminosulfonylalkyl group which may have the above-described substituentand a sulfonyl group. Examples of the aminosulfonylalkylsulfonyl groupinclude aminosulfonylmethylsulfonyl and aminosulfonylethylsulfonyl.

[0305] A³ also represents a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent. Examples of the saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group include cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenylgroups. Where the group has plural structural isomers as thecyclopentenyl group, they are all embraced in it.

[0306] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triadinyl.Where the group has plural structural isomers as pyranyl, they are allembraced in it.

[0307] When A³ represents a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, B³ represents a single bond, a carbonyl group, an alkylenegroup, a carbonylalkyl group,

[0308] a carbonylalkyloxy group or an alkylenecarbonyloxy group.Accordingly, the group A³-B³—, for example, represents a group as shownin the following Class (B):

[0309] Class (B):

[0310] a saturated or unsaturated 5- or 6-membered cyclic hydrocarbongroup or heterocyclic group which may have a substituent,

[0311] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent and a carbonyl group,

[0312] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent and an alkylene group,

[0313] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, a carbonyl group and an alkylene group,

[0314] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, a carbonyl group, an alkylene group and an oxygen atom,

[0315] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, an alkylene group and a carbonyl group,

[0316] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, an alkylene group, a carbonyl group and an oxygen atom, andthe like.

[0317] A description will next be made of the groups shown in Class (B).

[0318] In the group formed of a saturated or unsaturated 5 or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent and a carbonyl group, examples of the group formed of thecyclic hydrocarbon group and a carbonyl group includecyclopentylcarbonyl and phenylcarbonyl; while those of the group formedof the heterocyclic group and a carbonyl group include furylcarbonyl,thienylcarbonyl and pyridylcarbonyl groups.

[0319] In the group formed of a saturated or unsaturated 5 or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent and an alkylene group, the “group formed of a cyclichydrocarbon group and an alkylene group” means a group formed of theabove-described cyclic hydrocarbon group and C₁₋₆ alkylene group, forexample, cyclohexylmethyl and benzyl, while the “group formed of aheterocyclic group and an alkylene group” means a group formed of theabove-described heterocyclic group and linear, branched or cyclic C₁₋₆alkylene group, for example, furylmethyl, thienylethyl andpyridylpropyl.

[0320] In the group formed of a saturated or unsaturated 5 or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, a carbonyl group and an alkylene group, the “group formedof a cyclic hydrocarbon group, a carbonyl group and an alkylene group”means a group formed of the above-described cyclic hydrocarbon group, acarbonyl group and the above-described linear, branched or cyclic C₁₋₆alkylene group, for example, cyclopentadienylcarbonylmethyl andphenylcarbonylethyl, while the “group formed of a heterocyclic group, acarbonyl group and an alkylene group” means a group formed of theabove-described heterocyclic group, a carbonyl group and a linear,branched or cyclic C₁₋₆ alkylene group, for example,furylcarbonylmethyl, thienylcarbonylethyl and pyridylcarbonylpropyl.

[0321] In the group formed of a saturated or unsaturated 5 or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, a carbonyl group, an alkylene group and an oxygen atom, the“group formed of a cyclic hydrocarbon group, a carbonyl group, analkylene group and an oxygen atom” means a group composed of theabove-described group, which is composed of a cyclic hydrocarbon group,carbonyl group and alkylene group, and an oxygen atom, for example,cyclopentylcarbonylmethoxy and phenylcarbonylethoxy, while the “groupformed of a heterocyclic group, a carbonyl group, an alkylene group andan oxygen atom” means a group composed of the above-described group,which is composed of a heterocyclic group, a carbonyl group and analkylene group, and an oxygen atom, for example, furylcarbonylmethoxy,thienylcarbonylethoxy and pyridylcarbonylpropoxy.

[0322] In the group formed of a saturated or unsaturated 5 or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, an alkylene group and a carbonyl group, “the group formedof a cyclic hydrocarbon group, an alkylene group and a carbonyl group”means a group composed of the above-described group, which is formed ofa cyclic hydrocarbon group and an alkylene group, and a carbonyl group,for example, cyclohexylmethylcarbonyl and phenylethylcarbonyl, while“the group formed of a heterocyclic group, an alkylene group and acarbonyl group” means a group composed of the above-described group,which is formed of a heterocyclic group and an alkylene group, and acarbonyl group, for example, furylmethylcarbonyl, thienylethylcarbonyland pyridylpropylcarbonyl.

[0323] In the group formed of a saturated or unsaturated 5 or 6-memberedcyclic hydrocarbon group or heterocyclic group which may have asubstituent, an alkylene group, a carbonyl group and an oxygen atom,“the group formed of a cyclic hydrocarbon group, an alkylene group, acarbonyl group and an oxygen atom” means a group composed of theabove-described group, which is formed of a cyclic hydrocarbon group, analkylene group and a carbonyl group, and an oxygen atom, for example,cyclohexadienylmethylcarbonyloxy and phenylethylcarbonylyoxy, while “thegroup formed of a heterocyclic group, an alkylene group, a carbonylgroup and an oxygen atom” means a group composed of the above-describedgroup, which is formed of a heterocyclic group, an alkylene group and acarbonyl group, and an oxygen atom such as furylmethylcarbonyloxy,thienylethylcarbonyloxy and pyridylpropylcarbonyloxy.

[0324] As examples of a substituent which can be substituted for thesaturated or unsaturated 5- or 6-membered cyclic hydrocarbon group orheterocyclic group, those as shown in Class (3) can be given. The numberof the substituents which can be replaced is 1 to 3.

[0325] Class (3):

[0326] a hydroxyl group,

[0327] an alkyl group,

[0328] an alkoxyl group,

[0329] a hydroxyalkyl group,

[0330] an alkoxyalkyl group,

[0331] a halogen atom,

[0332] a cyano group,

[0333] a nitro group,

[0334] a carboxyl group,

[0335] an alkoxycarbonyl group,

[0336] a formyl group,

[0337] a heteroaryl group,

[0338] a heteroarylalkyl group,

[0339] an alkylimino group,

[0340] an amidino group,

[0341] a guanidino group,

[0342] an amino(hydroxyimino)alkyl group,

[0343] an amino(alkoxyimino)alkyl group,

[0344] an amino(aryloxyimino)alkyl group,

[0345] an amino group which may have one or two substituents,

[0346] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0347] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0348] an aminocarbonylalkyloxy group which may have, at the aminomoiety thereof, one or two substituents,

[0349] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents,

[0350] an aminoalkyloxy group which may have, at the amino moietythereof, one or two substituents,

[0351] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0352] an aminoalkylcarbonyloxy group which may have, at the aminomoiety thereof, one or two substituents, and an oxygen atom.

[0353] A description will next be made of the substituents which can bereplaced for the saturated or unsaturated 5 or 6-membered cyclichydrocarbon or heterocyclic group in Class (3).

[0354] The alkyl group, alkoxyl group, hydroxyalkyl group,

[0355] alkoxyalkyl group, halogen atom, alkoxycarbonyl group,aminocarbonyl group which may have, at the amino moiety thereof, one ortwo substituents, aminoalkyl group which may have, at the amino moietythereof, one or two substituents, aminocarbonylalkyl group which mayhave, at the amino moiety thereof, one or two substituents,aminocarbonylalkyloxy group which may have, at the amino moiety thereof,one or two substituents, aminoalkylcarbonyl group which may have, at theamino moiety thereof, one or two substituents, and aminoalkylcarbonyloxygroup which may have, at the amino moiety thereof, one or twosubstituents have the same meanings as described above.

[0356] The “heteroaryl group” means a monovalent aromatic group havingat least one hetero atom. Examples include pyridyl, furyl and thienyl.

[0357] The “heteroarylalkyl group” means a group formed of theabove-described heteroaryl group and a linear, branched or cyclic C₁₋₆alkylene group. Examples include pyridylmethyl, furylethyl andthienylmethyl.

[0358] The “alkylimino group” means a divalent group formed of a linear,branched or cyclic C₁₋₆ alkyl group and a nitrogen atom. Examplesinclude methylimino and ethylimino.

[0359] The “amino(hydroxyimino)alkyl group” means a group having aminoand hydroxyimino groups bonded to the same carbon atom of a linear,branched or cyclic C₁₋₆ alkyl group. Examples includeamino(hydroxyimino)methyl and amino(hydroxyimino)ethyl.

[0360] The “amino(alkoxyimino)alkyl group” means a group having aminoand alkoxyimino groups bonded to the same carbon atom of a linear,branched or cyclic C₁₋₆ alkyl group. Here, the “alkoxyimino group” meansa divalent group formed of the above-described alkoxyl group and animino group. Examples of the amino(alkoxyimino)alkyl group includeamino(methoxyimino)methyl and amino(ethoxyimino)methyl.

[0361] The “amino(aryloxyimino)alkyl group” means a group having aminoand aryloxyimino groups bonded to the same carbon atom of a linear,branched or cyclic C₁₋₆ alkyl group. Here, the “aryloxyimino group”means a divalent group formed of aryl and imino groups. Examples of thearyl group usable here include phenyl, naphthyl, anthryl andphenanthryl. Examples of the amino(aryloxyimino)alkyl group includeamino(phenoxyimino)methyl and amino(naphthyloxyimino)methyl.

[0362] The “aminoalkyloxy group which may have, at the amino moietythereof, one or two substituents” means a group formed of an amino grouphaving a substituent, a linear, branched or cyclic C₂₋₆ alkylene groupand an oxygen atom. Examples of the aminoalkyloxy group includeaminoethyloxy and aminopropyloxy. Examples of the group which can besubstituted for the amino moiety include those exemplified above.

[0363] In the case of the cyclic hydrocarbon group, an oxygen atom canserve as a substituent when the corresponding keto compound is formed,while, in the case of the heterocyclic group or dicyclic or tricyclicfused ring group, an oxygen atom can serve as a substituent when theoxygen atom is bonded to a nitrogen or sulfur atom forming the ring andthe corresponding N-oxide or S-oxide or keto compound is formed.

[0364] In the present invention, when R¹⁵ is not coupled with R¹⁶ or R¹⁷to form a C₁₋₃ alkylene or alkenylene group, preferred examples of R¹⁵include a hydrogen atom, an alkyl group, a hydroxyalkyl group and agroup A³-B³—.

[0365] In R¹⁶ and R¹⁷, examples of the halogen atom include fluorine,chlorine, bromine and iodine.

[0366] The “alkyl group” means a linear, branched or cyclic C₁₋₈ alkylgroup. Examples include methyl, ethyl, isopropyl, cyclopropyl, heptyland octyl.

[0367] The “hydroxyalkyl group” means a group formed of a hydroxyl groupand a linear, branched or cyclic C₁₋₈ alkylene group. Examples includehydroxymethyl and hydroxyethyl.

[0368] The “alkoxyalkyl group” means a group formed of theabove-described alkyl group, an oxygen atom and a linear, branched orcyclic C₁₋₈ alkylene group. Examples include methoxymethyl, methoxyethyland ethoxymethyl.

[0369] When R¹⁶ or R¹⁷ is coupled with R¹⁵ to form a C₁₋₃ alkylene oralkenylene group, the following group:

[0370] means the following group:

[0371] or the like.

[0372] In the present invention, when R¹⁶ or R¹⁷ is not coupled with R¹⁵to form a C₁₋₃ alkylene or alkenylene group, a hydrogen atom and alkylgroup are preferred as R¹⁶ or R¹⁷.

[0373] In the present invention, it is preferred that R¹⁵ and R¹⁶ or R¹⁷are coupled together to form a C₁₋₃ alkylene or alkenylene group.

[0374] R¹⁸ and R¹⁹ each independently represents a hydrogen atom, ahydroxyl group, a halogen atom, a halogenoalkyl group, an alkyl group,an alkoxyl group, an alkenyl group, an alkynyl group which may besubstituted with an alkylsilyl group as a protecting group, atrifluoromethyl group, a cyano group, an amino group, an aminoalkylgroup, an alkylaminoalkyl group, an amidino group, a hydroxyamidinogroup or an alkoxycarbonylamidino group (with the proviso that R¹⁸ andR¹⁹ do not represent a hydrogen atom at the same time).

[0375] In R¹⁸ and R¹⁹, the halogen atom, halogenoalkyl group, alkylgroup, alkoxyl group, alkenyl group and aminoalkyl group mean the samemeaning as described above.

[0376] The “alkylaminoalkyl group” means a group having one or twolinear, branched or cyclic alkyl groups substituted with the amino groupof the aminoalkyl moiety and examples include methylaminomethyl andethylmethylaminomethyl.

[0377] The “alkynyl group which may be substituted with an alkylsilylgroup as a protecting group” means an alkynyl group which may besubstituted with an alkylsilyl group such as trimethylsilyl,triethylsilyl, tertiary butyldimethylsilyl or dimethylphenylsilyl groupas a protecting group.

[0378] In the present invention, as R¹⁸ or R¹⁹, a halogen atom andalkynyl group are preferred, with a hydrogen atom, chlorine atom,bromine atom and ethynyl group are particularly preferred.

[0379] X³ in the group:

[0380] means a nitrogen atom or a group ═C(R¹⁰⁰)—

[0381] (wherein, R¹⁰⁰ represents a hydrogen atom, a halogen atom, analkyl group, an alkoxycarbonyl group, an aralkyloxycarbonylalkyl group,an alkoxycarbonylalkyl group, a nitro group, an amino group which mayhave a protecting group or an aminoalkyl group which may have, at theamino moiety thereof, a protecting group).

[0382] The halogen atom, alkyl group, alkoxycarbonyl group,aryloxycarbonylalkyl group, alkoxycarbonylalkyl group,aryloxycarbonylalkyl group in R¹⁰⁰ have the same meanings as describedabove, respectively. The amino group which may have a protecting groupor aminoalkyl group which may have, at the amino moiety thereof, aprotecting group mean amino group and aminoalkyl groups which may havean ordinarily known protecting group, respectively.

[0383] X⁴ represents an oxygen atom, a sulfur atom or a group —N-(R¹⁰¹)—

[0384] (wherein R¹⁰¹ means a hydrogen atom, an alkyl group, analkoxycarbonyl group, an aralkyloxycarbonyl group, analkoxycarbonylalkyl group, an alkylsulfonyl group or an arylsulfonylgroup).

[0385] The alkyl group, alkoxycarbonyl group, aralkyloxycarbonyl group,alkoxycarbonylalkyl group, alkylsulfonyl group and arylsulfonyl group inR¹⁰¹ have the same meanings as described above, respectively.

[0386] X⁵ and X⁸ each independently represents a nitrogen atom or agroup —C(R¹⁰²)

[0387] (wherein, R¹⁰² represents a hydrogen atom or a halogen atom) andthe halogen atom in R¹⁰² has the same meaning as described above.

[0388] X⁶ and X⁷ each independently represents a nitrogen atom or

[0389] a group —C(R¹⁰³)—

[0390] (wherein R¹⁰³ represents a hydrogen atom, a hydroxyl group, ahalogen atom, a halogenoalkyl group, an alkyl group, an alkoxyl group,alkenyl group, alkynyl group which may be substituted by an alkylsilylgroup as a protecting group, a cyano group, an amino group, anaminoalkyl group, an alkylaminoalkyl group, an amidino group, ahydroxyamidino group or an alkoxycarbonylamidino group).

[0391] The halogen atom, halogenoalkyl group, alkyl group, alkoxylgroup, alkenyl group, alkynyl group which may be substituted by analkylsilyl group as a protecting group, aminoalkyl group,alkylaminoalkyl group alkoxycarbonylamidino group in R¹⁰³ have the samemeanings as described above.

[0392] It is preferred that the group:

[0393] means any one of the following groups:

[0394] [wherein R¹⁰¹ and R¹⁰³ have the same meanings as described aboveand R^(103′) means those similar to R¹⁰³].

[0395] As R¹⁰¹, a hydrogen atom is particularly preferred. It ispreferred that either one of R¹⁰³ and R^(103′) represents a halogenatom, an alkynyl group, an amidino group, a hydroxyamidino group or analkoxycarbonylamidino group, with the halogen atom, ethynyl group,amidino group, hydroxyamidino group and methoxycarbonylamidino groupbeing particularly preferred.

[0396] In the group:

[0397] X⁹ and X¹² each independently represents a nitrogen atom or agroup —C(R¹⁰⁴)—

[0398] (wherein R¹⁰⁴ represents a hydrogen atom or a halogen atom) andthe halogen atom as R¹⁰⁴ is similar to that described above.

[0399] X¹⁰ and X¹¹ each independently represents a nitrogen atom or

[0400] a group —C(R¹⁰⁵)—

[0401] (wherein R¹⁰⁵ represents a hydrogen atom, a hydroxyl group, ahalogen atom, a halogenoalkyl group, an alkyl group, an alkoxyl group,alkenyl group, alkynyl group which may be substituted by an alkylsilylgroup as a protecting group, a cyano group, an amino group, anaminoalkyl group, an alkylaminoalkyl group, an amidino group, ahydroxyamidino group or an alkoxycarbonylamidino group).

[0402] The halogen atom, halogenoalkyl group, alkyl group, alkoxylgroup, alkenyl group, alkynyl group which may be substituted by analkylsilyl group as a protecting group, aminoalkyl group,alkylaminoalkyl group alkoxycarbonylamidino group in R¹⁰⁵ have the samemeanings as described above.

[0403] The group:

[0404] preferably represents the following group:

[0405] [wherein R¹⁰⁵ has the same meanings as described above andR^(105′) is similar to that described as R¹⁰⁵].

[0406] It is preferred that either one of R¹⁰⁵ and R^(105′) represents ahalogen atom, an alkynyl group, an amidino group, a hydroxyamidino groupor an alkoxycarbonylamidino group, with the halogen atom, ethynyl group,amidino group, hydroxyamidino group and methoxycarbonylamidino groupbeing particularly preferred.

[0407] <About the Group Q¹>

[0408] Q¹ represents a saturated or unsaturated 5- or 6-membered cyclichydrocarbon group which may have a substituent, a saturated orunsaturated 5- or 6-membered heterocyclic group which may have asubstituent, a saturated or unsaturated dicyclic fused ring group whichmay have a substituent, or a saturated or unsaturated tricyclic fusedring group which may have a substituent.

[0409] Here, examples of the saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group include cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.When the group has plural structural isomers as cyclopentenyl, they areall embraced in it.

[0410] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl,imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl,thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl,pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl,pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl,morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl,tetrazinyl, triazolyl and triazinyl. Where the group has pluralstructural isomers as pyranyl, they are all embraced in it.

[0411] The “saturated or unsaturated, dicyclic fused ring group whichmay have a substituent” or “saturated or unsaturated, tricylic fusedring group which may have a substituent” has the same meaning as definedin the description of the group Q^(A). More specifically, it means: 1) agroup obtained by the condensation of saturated or unsaturated 5- or6-membered cyclic hydrocarbon groups which may have a substituent, 2) agroup obtained by the condensation of a saturated or unsaturated 5- or6-membered cyclic hydrocarbon group which may have a substituent and asaturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent and 3) a group obtained by the condensation ofsaturated or unsaturated 5- or 6-membered heterocyclic groups which mayhave a substituent. Examples of the group 1) include indenyl, indanyl,naphthyl, tetrahydronaphthyl, anthryl and phenanthryl; those of thegroup 2) include benzofuranyl, indolyl, indolinyl, quinolyl,benzodiazinyl, tetrahydroisoquinolyl, benzothiazolyl,tetrahydrothiazolyl and isoindolyl; and those of the group 3) includenaphthyridinyl, furanopyridyl, thienopyridyl, tetrahydrothienopyridyl,pyrazolopyridyl, thiazolopyridyl, tetrahydrothiazolopyridyl,thiazolopyrazyl, tetrahydrothiazolopyrazyl, thiazolopyridazyl,tetrahydropyridopyridyl, thiazolopyridazinyl,tetrahydrothiazolopyridazinyl, pyrrolopyridyl, tetrahydropyrrolopyridyl,dihydropyridoquinazolinyl, pyridopyrimidinyl,tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl,furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl andtetrahydrooxazolopyridyl.

[0412] Examples of the substituent which can be replaced for theabove-described saturated or unsaturated 5- or 6-membered cyclichydrocarbon group, saturated or unsaturated 5- or 6-memberedheterocyclic group, saturated or unsaturated dicyclic fused ring group,or saturated or unsaturated tricyclic fused ring group include thegroups shown in the below-described Class (4). The number of thereplaceable substituents ranges from 1 to 7.

[0413] Class (4):

[0414] a hydroxyl group,

[0415] an alkyl group,

[0416] an alkenyl group,

[0417] a halogenoalkyl group,

[0418] a halogenoalkenyl group,

[0419] an alkoxyl group,

[0420] a hydroxyalkyl group,

[0421] an alkoxyalkyl group,

[0422] a halogen atom,

[0423] a cyano group,

[0424] a nitro group,

[0425] a carboxyl group,

[0426] an alkoxycarbonyl group,

[0427] a formyl group,

[0428] a heteroaryl group,

[0429] a heteroarylalkyl group,

[0430] an alkylimino group,

[0431] an alkylsulfonyl group,

[0432] an amidino group,

[0433] a guanidino group,

[0434] an amino(hydroxyimino)alkyl group,

[0435] an amino(alkoxyimino)alkyl group,

[0436] an amino(aryloxyimino)alkyl group,

[0437] a hydroxyimino group,

[0438] an alkoxyimino group,

[0439] an aminoimino group which may have, at the amino moiety thereof,one or two substituents,

[0440] an amino group which may have one or two substituents,

[0441] an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0442] an aminocarbonylalkyl group which may have, at the amino moietythereof, one or two substituents,

[0443] an aminocarbonylalkyloxy group which may have, at the aminomoiety thereof, one or two substituents,

[0444] an aminosulfonyl group which may have, at the amino moietythereof, one or two substituents,

[0445] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents,

[0446] an aminoalkyloxy group which may have, at the amino moietythereof, one or two substituents,

[0447] an aminoalkylcarbonyl group which may have, at the amino moietythereof, one or two substituents,

[0448] an aminoalkylcarbonyloxy group which may have, at the aminomoiety thereof, one or two substituents,

[0449] an oxygen atom,

[0450] a trifluoromethylsulfonyloxy group,

[0451] a trifluoromethylsulfonyloxyalkenyl group,

[0452] a boric acid group (—B(OH₂)),

[0453] a saturated or unsaturated 5- or 6-membered cyclic hydrocarbongroup which may have 1 to 3 substituents selected from the groupconsisting of halogen, hydroxyl, amino, alkoxyl, alkyl, cyano, nitro,carboxyl, alkoxycarbonyl, aminocarbonyl which may have, at the aminomoiety thereof, one or two substituents, aminosulfonyl which may have,at the amino moiety thereof, one or two substituents, aminoalkyl whichmay have, at the amino moiety thereof, one or two substituents andtrifluoromethyl, and saturated or unsaturated 5- or 6-memberedheterocyclic group which may have 1 to 3 substituents selected from thegroup consisting of halogen, hydroxyl, amino, alkoxyl, alkyl, cyano,nitro, carboxyl, alkoxycarbonyl, aminocarbonyl which may have, at theamino moiety thereof, one or two substituents, aminosulfonyl which mayhave, at the amino moiety thereof, one or two substituents, aminoalkylwhich may have, at the amino moiety thereof, one or two substituents andtrifluoromethyl.

[0454] The substituents in Class (4) have the same meanings as describedin Classes (1) to (3) of the description of the group Q^(A).

[0455] In the present invention, preferred examples of Q¹ include acyclopentyl group which may have a substituent, cyclohexyl group whichmay have a substituent, cyclopentenyl group which may have asubstituent, cyclohexenyl group which may have a substituent, phenylgroup which may have a substituent, pyrrolidinyl group which may have asubstituent, piperidinyl group which may have a substituent, imidazolylgroup which may have a substituent, thiazolyl group which may have asubstituent, thiadiazolyl group which may have a substituent, pyridylgroup which may have a substituent, pyrimidinyl group which may have asubstituent, pyridazinyl group which may have a substituent,thiazolydinyl group which may have a substituent, morpholinyl groupwhich may have a substituent, piperazinyl group which may have asubstituent, thiomorpholinyl group which may have a substituent,pyrrolyl group which may have a substituent, thienyl group which mayhave a substituent, furanyl group which may have a substituent,tetrahydropyrimidinyl group which may have a substituent,tetrahydrofuranyl group which may have a substituent, tetrahydrothienylgroup which may have a substituent, sulforanyl group which may have asubstituent, imidazolinyl group which may have a substituent,thiazolinyl group which may have a substituent, oxazolyl group which mayhave a substituent, oxadiazinyl group which may have a substituent,triazinyl group which may have a substituent, tetrazinyl group which mayhave a substituent, pyrazinyl group which may have a substituent,pyrazolyl group which may have a substituent, pyrazolinyl group whichmay have a substituent, pyrazolidinyl group which may have asubstituent, thienopyridyl group which may have a substituent,tetrahydrothienopyridyl group which may have a substituent,thiazolopyridyl group which may have a substituent,tetrahydrothiazolopyridyl group which may have a substituent,pyranothiazolyl group which may have a substituent,dihydropyranothiazolyl group which may have a subsituent,thiazolopyridadinyl group which may have a substituent,tetrahydrothiazolopyridadinyl group which may have a substituent,furopyridyl group which may have a substituent, tetrahydrofuropyridylgroup which may have a substituent, oxazolopyridyl group which may havea substituent, and tetrahydrooxazolopyridyl group which may have asubstituent.

[0456] Examples of the substituent include a hydroxyl group, an alkylgroup, a hydroxyalkyl group, a halogen atom, a cyano group, a nitrogroup, a carboxyl group, an alkoxycarbonyl group, a formyl group, analkylsulfonyl group, an amino group which may have one or twosubstituents, an aminosulfonyl group which may have, at the amino moietythereof, one or two substituents, an aminoalkyl group which may have, atthe amino moiety thereof, one or two substituents, an oxygen atom, atrifluoromethyl group, a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have 1 to 3 substituents selectedfrom the group consisting of a halogen atom, a hydroxyl group, an aminogroup, an alkoxyl group, an alkyl group, a cyano group, a nitro group, acarboxyl group, an alkoxycarbonyl group, an aminocarbonyl group whichmay have, at the amino moiety thereof, one or two substituents, anaminosulfonyl group which may have, at the amino moiety thereof, one ortwo substituents, an aminoalkyl group which may have, at the aminomoiety thereof, one or two substituents and a trifluoromethyl group, anda saturated or unsaturated 5- or 6-membered heterocyclic group which mayhave 1 to 3 substituents selected from the group consisting of a halogenatom, a hydroxyl group, an amino group, an alkoxyl group, an alkylgroup, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonylgroup, an aminocarbonyl group which may have, at the amino moietythereof, one or two substituents, an aminosulfonyl group which may have,at the amino moiety thereof, one or two substituents, an aminoalkylgroup which may have, at the amino moiety thereof, one or twosubstituents and a trifluoromethyl group

[0457] <About Q²>

[0458] Q² represents a single bond, an oxygen atom, a sulfur atom, alinear or branched C₁₋₆ alkylene group, a linear or branched C₂₋₆alkenylene group, a linear or branched C₂₋₆ alkynylene group,

[0459] a group —N-(R¹)—CO—

[0460] (wherein, R¹ represents a hydrogen atom or an alkyl group),

[0461] a group-N-(R²)—(CH₂)_(m)—

[0462] (wherein, R represents a hydrogen atom or an alkyl group and mstands for an integer of 0 to 6), or

[0463] a group:

[0464] (which represents a divalent, saturated or unsaturated 5 or6-membered cyclic hydrocarbon group which may have a substituent, adivalent, saturated or unsaturated 5- or 6-membered heterocyclic groupwhich may have a substituent or a divalent, saturated or unsaturateddicyclic fused ring group which may have a substituent and +C means thebonding of the carbon atom of this group to Q¹),

[0465] In Q², examples of the linear or branched C₁₋₆ alkylene groupinclude methylene, ethylene, trimethylene, propylene, tetramethylene,butylene, pentamethylene and hexamethylene.

[0466] Examples of the linear or branched C₂₋₆ alkenylene group includevinylene, propenylene, butenylene and pentenylene. There is noparticular limitation on the position of the double bond.

[0467] Examples of the linear or branched C₂₋₆ alkynylene group includepropynylene, butynylene, pentynylene and hexynylene.

[0468] The group of the following formula:

[0469] means a divalent, saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent a divalent,saturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent or a divalent, saturated or unsaturated dicyclicfused ring group which may have a substituent and ←C means the bondingof the carbon atom of this group to Q¹. Examples of the group includedivalent groups derived from thiophene, furan, pyran, pyrrole,pyrrolidine, pyrroline, imidazole, imidazoline, imidazolidine, pyrazole,pyrazolidine, thiazole, oxazole, oxathiolane, benzene, pyridine,piperidine, piperazine, morpholine, thiomorpholine, pyrazine,pyrimidine, pyridazine, triazine, tetrazine, thiadiazine, dithiazine,cyclopentane, cyclopetene, cyclopentadiene, cyclohexane, cyclohexene andthey may have a substituent. Examples of the substituent are similar tothose exemplified in Class (4).

[0470] The alkyl group in R¹ or R² of the group —N-(R¹)—CO— or—N-(R²)—(CH₂)_(m)— means a linear, branched or cyclic C₁₋₆ alkyl group.Examples include methyl, ethyl, isopropyl and cyclopropyl. As the group—N-(R¹)-CO—, a group ←N-(R¹)—CO— (wherein ← means the bonding of thenitrogen atom of this group to Q¹) is preferred, while as the group—N-(R²)—(CH₂)_(m)—, a group ←N-(R²)—(CH₂)_(m)— (wherein ← means thebonding of the nitrogen atom of this group to Q¹) is preferred.

[0471] In the present invention, Q² preferably represents a single bond,a carbonyl group or a group of the following formula:

[0472] and as the group represented by the following formula:

[0473] divalent groups derived from benzene, pyrimidine,tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine,imidazole, imidazoline, thiazole, thiazoline, furan, thiophene, pyrrole,oxazole, oxazoline, thiadiazole, cyclopentane, cyclopentene, cyclohexaneor cyclohexene.

[0474] <About Q³>

[0475] In R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ as the substituents in Q³,the alkyl, alkoxyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkyloxy,hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, formylalkyl,formylalkylcarbonyl, formylalkylsulfonyl, alkylcarbonyl, alkylsulfonyl,alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl,carboxyalkylcarbonyl, carboxyalkylsulfonyl, carboxyalkylcarbonylalkyl,carboxyalkylsulfonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkylsulfonyl, amino whichmay have 1 to 2 substituents, aminoalkyl which may have, at the aminomoiety thereof, one or two substituents, aminoalkyloxy which may have,at the amino moiety thereof, one or two substituents, aminoalkylcarbonylwhich may have, at the amino moiety thereof, one or two substituents,aminoalkylcarbonyloxy which may have, at the amino moiety thereof, oneor two substituents, aminocarbonyl which may have, at the amino moietythereof, one or two substituents, aminocarbonylalkyl which may have, atthe amino moiety thereof, one or two substituents, andaminocarbonylalkyloxy which may have, at the amino moiety thereof, oneor two substituents have the same meanings as described above in R¹⁵ ofthe description of the group Q^(A).

[0476] The “alkoxyalkyloxy group” means a group formed of theabove-described alkoxyalkyl group and an oxygen atom and examplesinclude methoxymethyloxy, methoxyethyloxy and ethoxymethyloxy.

[0477] The “carboxyalkyloxy group” means a group formed of theabove-described carboxyalkyl group and an oxygen atom and examplesinclude carboxymethoxyl and carboxyethoxyl.

[0478] The “carboxyalkyloxy group” means a group formed of theabove-described carboxylalkyl group and an oxygen atom and examplesinclude carboxymethoxyl and carboxyethoxyl.

[0479] The “alkoxycarbonylalkyloxy group” means a group formed of theabove-described alkoxycarbonylalkyl group and an oxygen atom andexamples include methoxycarbonylethyl and ethoxycarbonylethyl.

[0480] The “alkylsulfonylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent” means a group formed of theabove-described alkylsulfonyl group, an imino group which may have onesubstituent and a carbonyl group and examples includemethylsulfonylaminocarbonylmethyl.

[0481] The “arylsulfonylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent” means a group formed of an arylgroup, a sulfonyl group, an imino group which may have one substituentand a carbonyl group and examples includephenylsulfonylaminocarbonylmethyl.

[0482] The “aminosulfonylalkyl group which may have, at the amino moietythereof, one or two substituents” means a group formed of an amino groupwhich may have one or two substituents, a sulfonyl group and a linear,branched or cyclic C₁₋₆ alkylene group and examples includeaminosulfonylmethyl.

[0483] The “cyanoalkyl group” means a group formed of a cyano group anda linear, branched or cyclic C₁₋₆ alkylene group.

[0484] The “alkylcarbonyloxyalkyl group” menas a group formed of theabove-described alkylcarbonyl group, an oxygen atom and a linear,branched or cyclic C₁₋₆ alkylene group and examples includemethylcarbonyloxyethyl.

[0485] The “alkoxyalkylaminocarbonylalkyl group which may have, at theamino moiety thereof, one substituent” means a group formed of theabove-described alkoxyalkyl group, an imino group which may have onesubstituent and a carbonyl group and examples includeethoxymethylaminocarbonylmethyl.

[0486] In the group A¹-B¹—, A¹ represents a saturated or unsaturated 5-or 6-membered cyclic hydrocarbon group which may have a substituent or asaturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent. Here, examples of the saturated or unsaturated 5- or6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.When the group has various structural isomers as the cyclopentenylgroup, they are all embraced in it.

[0487] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinyl.Where the group has plural structural isomers as the pyranyl group, theyare all embraced in it.

[0488] B¹ represents a single bond, carbonyl group, alkylene group,carbonylalkyl group, a group —O—C₁₋₆ alkylene, a group —COO—C₁₋₆alkylene, a group —NHCO— or a group —NHCO—C₁₋₆ alkylene.

[0489] Examples of the group A¹-B¹— include the following groups:

[0490] a saturated or unsaturated 5- or 6-membered cyclic hydrocarbongroup which may have a substituent,

[0491] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and a carbonyl group,and

[0492] a group formed of a saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent and an alkylenegroup.

[0493] Each of R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, and R¹⁰ and R¹¹ arecoupled together with a carbon atom which constitutes the ring andrepresents a saturated or unsaturated 5- to 7-membered cyclichydrocarbon group which may have a substituent or a saturated orunsaturated 5- to 7-membered heterocyclic group which may have asubstituent. Here, examples of the saturated or unsaturated 5- or7-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.When the group has various structural isomers as the cyclopentenyl, theyare all embraced in it.

[0494] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinyl.Where the group has plural structural isomers as the pyranyl, they areall embraced in it.

[0495] In R⁹ or R¹² as the substituent in Q³, the alkyl, hydroxyalkyl,alkoxyl, hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, alkoxyalkyl,alkoxyalkylcarbonyl, alkoxyalkylsulfonyl, formylalkyl,formylalkylcarbonyl, formylalkylsulfonyl, alkylcarbonyl, alkylsulfonyl,alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkylcarbonyl,carboxyalkylsulfonyl, carboxyalkylcarbonylalkyl,carboxyalkylsulfonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkylsulfonyl, amino whichmay have 1 to 2 substituents, aminoalkyl which may have, at the aminomoiety thereof, aminoalkyloxy which may have, at the amino moietythereof, aminoalkylcarbonyl which may have, at the amino moiety thereof,one or two substituents, aminoalkyloxycarbonyl which may have, at theamino moiety thereof, 1 or 2 substituents, aminocarbonyl which may have,at the amino moiety thereof, one or two substituents, aminocarbonylalkylwhich may have, at the amino moiety thereof, one or two substituents,and aminocarbonyloxyalkyl which may have, at the amino moiety thereof,one or two substituents have the same meanings as described in Q^(A).

[0496] In the group A²-B²—, A² represents a saturated or unsaturated 5-or 6-membered cyclic hydrocarbon group which may have a substituent or asaturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent. Here, examples of the saturated or unsaturated 5- or6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.When the group has plural structural isomers as the cyclopentenyl, theyare all embraced in it.

[0497] The saturated or unsaturated 5- or 6-membered heterocyclic groupis a cyclic group having at least one hetero atom. Examples of thehetero atom include oxygen, nitrogen and sulfur. Examples of thesaturated or unsaturated 5- or 6-membered heterocyclic group includefuryl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl,oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl,furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl,piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl,thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinyl.Where the group has plural structural isomers as the pyranyl, they areall embraced in it.

[0498] B² represents a single bond, carbonyl group, alkylene group,carbonylalkyl group, a group —O—C₁₋₆ alkylene, a group —COO—C₁₋₆alkylene, a group —NHCO— or a group —NHCO—C₁₋₆ alkylene.

[0499] Examples of the group A²-B²— include the following groups:

[0500] a saturated or unsaturated 5- or 6-membered heterocyclic groupwhich may have a substituent, membered cyclic hydrocarbon group whichmay have a substituent and a carbonyl group, and

[0501] a group formed of a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and an alkylene group.

[0502] R⁹ and R⁷, R⁹ and R⁸, R¹² and R¹⁰ and R¹² and R¹¹ are eachcoupled together with the carbon atom which constitutes the ring and thenitrogen atom to which R⁹ or R¹² has been bonded and represent asaturated or unsaturated 5- to 7-membered heterocyclic group which mayhave a substituent. Here, the saturated or unsaturated 5- to 7-memberedheterocyclic group is a cyclic group which has at least one nitrogenatom and may have a hetero atom. Examples of the hetero atom includeoxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5-or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl,pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl,thiazolinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl,pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl,oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl,triazolyl and triazinyl. Where the group has plural structural isomersas the pyranyl, they are all embraced in it.

[0503] In the present invention, Q³ represents a group of the followingformula:

[0504] (wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ R¹¹, R¹², a, b, c, d, e,f, g, h and i have the same meanings as described above). Preferred asQ³ is a group of the following formula:

[0505] (wherein R³, R⁴, a, b and c have the same meanings as describedabove), of which the group wherein:

[0506] R³ and R⁴ each independently represents

[0507] a hydrogen atom,

[0508] a hydroxyalkyl group,

[0509] a cyanoalkyl group,

[0510] a carboxyl group,

[0511] a carboxyalkyl group,

[0512] an alkoxycarbonyl group,

[0513] an alkoxycarbonylalkyl group,

[0514] a carboxyalkylaminocarbonyl group,

[0515] a carboxyalkylaminocarbonylalkyl group,

[0516] an alkoxycarbonylalkylaminocarbonyl group,

[0517] an alkoxycarbonylalkylaminocarbonylamino group,

[0518] a carbamoyl group,

[0519] a monoalkylcarbamoyl group,

[0520] a dialkylcarbamoyl group,

[0521] a carbamoylalkyl group,

[0522] a monoalkylcarbamoylalkyl group,

[0523] a dialkylcarbamoylalkyl group,

[0524] a morpholinylcarbonyl group

[0525] a morpholinylcarbonylalkyl group,

[0526] a tetrazolylaminocarbonyl group,

[0527] a tetrazolylaminocarbonylalkyl group,

[0528] a tetrazolylalkyl group,

[0529] a tetrazolylalkylaminocarbonyl group, or atetrazolylalkylaminocarbonylalkyl group,

[0530] an aminoalkyl group which may have, at the amino moiety thereof,one or two substituents,

[0531] an alkylaminosulfonylalkyl group,

[0532] an oxopyrrolidinylalkyl group,

[0533] oxopiperidinylalkyl group, or

[0534] oxooxazolidinylalkyl group, and

[0535] a stands for 0, b stands for 0 and c stands for 2 is morepreferred.

[0536] <About T¹>

[0537] T¹ represents a carbonyl group,

[0538] a group —CH(R¹³)—

[0539] (in which R¹³ represents a hydrogen atom, an alkyl group, ahydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, analkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroarylgroup, a heteroarylalkyl group or an aminoalkyl group which may have, atthe amino moiety thereof, a substituent), or

[0540] a group —C(═NOR¹⁴)— or —C (═N—NHR^(14′))—

[0541] (in which R¹⁴ and R^(14′) each independently represents ahydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonylgroup, an aryl group, an aralkyl group, a heteroaryl group, aheteroarylalkyl group or an aminoalkyl group which may have, at theamino moiety thereof, a substituent).

[0542] Here, in R¹³ and R¹⁴, the alkyl, carboxyalkyl, alkoxycarbonyl,aryl, aralkyl, heteroaryl, heteroarylalkyl and aminoalkyl which mayhave, at the amino moiety thereof, a substituent have the same meaningsas described in Q^(A). In the present invention, a carbonyl group ispreferred as T¹.

[0543] The sulfonyl derivative of the present invention has opticalisomers or stereoisomers based on an asymmetric carbon atom. Theseoptical isomers and stereoisomers and mixtures thereof are all embracedin the present invention.

[0544] Although there is no particular limitation imposed on the salt ofthe sulfonyl derivative according to the present invention insofar as itis a pharmaceutically acceptable salt. Specific examples include saltsof a mineral acid such as hydrochloride, hydrobromide, hydroiodide,phosphate, nitrate and sulfate, salts of an organic sulfonic acid suchas benzoate, methanesulfonate, 2-hydroxyethanesulfonate andp-toluenesulfonate and salts of an organic carboxylic acid such asacetate, propanoate, oxalate, malonate, succinate, glutarate, adipate,tartrate, maleate, malate and mandelate. There is no particularlimitation imposed on the solvate insofar as it is pharmaceuticallyacceptable. Specific examples include hydrates and ethanolates.

[0545] The following are the preferred compounds as the sulfonylderivative of the present invention.

[0546]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[2-[(N,N-dimethyl)amino]ethyl]-4-methylthiazol-2-yl]carbonyl]piperazine

[0547]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[2-[(N,N-dimethyl)amino]ethyl]thiazol-2-yl]carbonyl]piperazine

[0548]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[3-[(N,N-dimethyl)amino]propyl]-4-methylthiazol-2-yl]carbonyl]piperazine

[0549]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[3-[(N,N-dimethyl)amino]propyl]thiazol-2-yl]carbonyl]piperazine

[0550]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[2-[(N,N-dimethyl)amino]ethyl]-4-methylthiazol-2-yl]carbonyl]piperazine

[0551]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[2-[(N,N-dimethyl)amino]ethyl]thiazol-2-yl]carbonyl]piperazine

[0552]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[3-[(N,N-dimethyl)amino]propyl]-4-methylthiazol-2-yl]carbonyl]piperazine

[0553]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[3-[(N,N-dimethyl)amino]propyl]thiazol-2-yl]carbonyl]piperazine

[0554] 1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[2-[(N,N-dimethyl)amino] ethyl]-4-methylthiazol-2-yl]carbonyl]piperazine

[0555]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[2-[(N,N-dimethyl)amino]ethyl]thiazol-2-yl]carbonyl]piperazine

[0556]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[3-[(N,N-dimethyl)amino]propyl]-4-methylthiazol-2-yl]carbonyl]piperazine

[0557]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[3-[(N,N-dimethyl)amino]propyl]thiazol-2-yl]carbonyl]piperazine

[0558]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0559]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-3-yl]thiazol-2-yl]carbonyl]piperazine

[0560]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-2-yl]thiazol-2-yl]carbonyl]piperazine

[0561]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-4-yl]thiazol2-yl]carbonyl]piperazine

[0562]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-3-yl]thiazol2-yl]carbonyl]piperazine

[0563]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-2-yl]thiazol2-yl]carbonyl]piperazine

[0564]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyrrolidin3-yl)thiazol-2-yl]carbonyl]piperazine

[0565]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(1-methylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0566]1-[[5-(1-Carbamoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[0567]1-[[5-(1-Acetoimidoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[0568]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-(pyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0569]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-(1-methylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0570]1-[[5-(1-Carbamolylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0571]1-[[5-(1-Acetoimidoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0572]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[(1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0573]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[(1-methyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0574]1-[[5-[(1-Carbamoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[0575]1-[[5-[(1-Acetoimidoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[0576]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0577]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0578]1-[[5-[(1-Carbamoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0579]1-[[5-[(1-Acetoimidoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0580]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazine

[0581]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0582]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0583]3-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0584]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)thiazol-2-yl]carbonyl]piperazine

[0585]2-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0586]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0587]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-3-yl]thiazol-2-yl]carbonyl]piperazine

[0588]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-2-yl]thiazol-2-yl]carbonyl]piperazine

[0589]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-4-yl]thiazol2-yl]carbonyl]piperazine

[0590]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-3-yl]thiazol2-yl]carbonyl]piperazine

[0591]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-2-yl]thiazol2-yl]carbonyl]piperazine

[0592]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0593]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(1-methylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0594]1-[[5-(1-Carbamoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[0595]1-[[5-(1-Acetoimidoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[0596]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-(pyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0597]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-(1-methylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0598]1-[[5-(1-Carbamoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0599]1-[[5-(1-Acetoimidoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0600]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[(1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0601]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[(1-methyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0602]1-[[5-[(1-Carbamoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[0603]1-[[5-[(1-Acetoimidoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[0604]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0605]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0606]1-[[5-[(1-carbamoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]2-[(N-methyl)carbamoyl]piperazine

[0607]1-[[5-[(1-Acetoimidoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]2-[(N-methyl)carbamoyl]piperazine

[0608]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazine

[0609]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-lyl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0610]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0611]3-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-lyl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0612]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)thiazol-2-yl]carbonyl]piperazine

[0613]2-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-lyl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0614]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0615]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-3-yl]thiazol-2-yl]carbonyl]piperazine

[0616]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[(1-methylpiperidin)-2-yl]thiazol-2-yl]carbonyl]piperazine

[0617]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0618]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-3-yl]thiazol2-yl]carbonyl]piperazine

[0619]4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methylpiperidin)-2-yl]thiazol2-yl]carbonyl]piperazine

[0620]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0621]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(1-methylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0622]1-[[5-(1-Carbamoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[0623]1-[[5-(1-Acetoimidoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[0624]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-(pyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0625]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-(1-methylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0626]1-[[5-(1-Carbamoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0627]1-[[5-(1-Acetoimidoylpyrrolidin-3-yl)thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0628]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[(1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0629]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[(1-methyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0630]1-[[5-[(1-Carbamoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[0631]1-[[5-[(1-Acetoimidoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[0632]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0633]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[[5-[(1-methyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]piperazine

[0634]1-[[5-[(1-Carbamoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0635]1-[[5-[(1-Acetoimidoyl-1,2,5,6-tetrahydropyridin)-4-yl]thiazol-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazine

[0636]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazine

[0637]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0638]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-3-yl)thiazol-2-yl]carbonyl]piperazine

[0639]3-[2-[[4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0640]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)thiazol-2-yl]carbonyl]piperazine

[0641]2-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-oxide

[0642]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[1,2-dihydro-2-oxo-6-(pyridin-4-yl)pyridin-3-yl]carbonyl]piperazine

[0643]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[1,2-dihydro-2-oxo-6-(pyridin-4-yl)pyridin-3-yl]carbonyl]piperazine

[0644]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[1,2-dihydro-2-oxo-6-(pyridin-4-yl)pyridin-3-yl]carbonyl]piperazine

[0645]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-pyridazin-3-yl]carbonyl]piperazine

[0646]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-pyridazin-3-yl]carbonyl]piperazine

[0647]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)pyridazin-3-yl]carbonyl]piperazine

[0648]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0649]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0650]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0651]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2,5-dihydro-5-oxo-6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0652]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0653]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0654]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0655]4-[3-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2-dihydro-2-oxopyridin-6-yl]pyridineN-oxide

[0656]4-[3-[[4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2-dihydro-2-oxopyridin-6-yl]pyridineN-oxide

[0657]4-[3-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2-dihydro-2-oxopyridin-6-yl]pyridineN-oxide

[0658]4-[6-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyridazin-3-yl]pyridineN-oxide

[0659]4-[6-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyridazin-3-yl]pyridineN-oxide

[0660]4-[6-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyridazin-3-yl]pyridineN-oxide

[0661]4-[6-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-3-yl]pyridineN-oxide

[0662]4-[6-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-3-yl]pyridineN-oxide

[0663]4-[6-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-3-yl]pyridineN-oxide

[0664]4-[3-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-2,5-dihydro-5-oxo-1,2,4-triazin-6-yl]pyridineN-oxide

[0665]4-[3-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-6-yl]pyridineN-oxide

[0666]4-[3-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-6-yl]pyridineN-oxide

[0667]4-[3-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-6-yl]pyridineN-oxide

[0668]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0669]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0670] 1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl] carbonyl]piperazine

[0671]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2-hydroxymethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0672]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(2-hydroxymethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0673]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2-hydroxymethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0674]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0675]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0676]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0677]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2,3-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0678]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(2,3-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0679]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2,3-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0680]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(3-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0681]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(3-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0682]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(3-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0683]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(3-fluoropyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0684]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(3-fluoropyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0685]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2-fluoropyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0686]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2,5-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0687]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(2,5-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0688]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2,5-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0689]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[0690]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[0691]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[0692]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-hydroxymethylpyridineN-oxide

[0693]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-hydroxymethylpyridineN-oxide

[0694]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-hydroxymethylpyridineN-oxide

[0695]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,6-dimethylpyridineN-oxide

[0696]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,6-dimethylpyridineN-oxide

[0697]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,6-dimethylpyridineN-oxide

[0698]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,3-dimethylpyridineN-oxide

[0699]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,3-dimethylpyridineN-oxide

[0700]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,3-dimethylpyridineN-oxide

[0701]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-3-methylpyridineN-oxide

[0702]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-3-methylpyridineN-oxide

[0703]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-3-methylpyridineN-oxide

[0704]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-3-fluoropyridineN-oxide

[0705]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-3-fluoropyridineN-oxide

[0706]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-fluoropyridineN-oxide

[0707]4-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,5-dimethylpyridineN-oxide

[0708]4-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,5-dimethylpyridineN-oxide

[0709]4-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,5-dimethylpyridineN-oxide

[0710]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)-3,4,5,6-tetrahydropyrimidin-5-yl]carbonyl]piperazine

[0711]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)-3,4,5,6-tetrahydropyrimidin-5-yl]carbonyl]piperazine

[0712]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)3,4,5,6-tetrahydropyrimidin-5-yl]carbonyl]piperazine

[0713]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5,6-dihydro-2-(pyridin-4-yl)oxazin-5-yl]carbonyl]piperazine

[0714]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5,6-dihydro-2-(pyridin-4-yl)oxazin-5-yl]carbonyl]piperazine

[0715]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5,6-dihydro-2-(pyridin-4-yl)oxazin-5-yl]carbonyl]piperazine

[0716]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8-[4-(pyridin-4-yl)benzoyl]-3,8-diazabicyclo[3.2.1]octane

[0717]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan]-8-yl]carbonyl]phenyl]pyridineN-oxide

[0718]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[4-(pyridin-4-yl)benzoyl]-3,8-diazabicyclo[3.2.1]octane

[0719]4-[4-[[[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy3,8-diazabicyclo[3.2.1]octan]-8-yl]carbonyl]phenyl]pyridineN-oxide

[0720]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy8-[4-(pyridin-4-yl)benzoyl]-3,8-diazabicyclo[3.2.1]octane

[0721]4-[4-[[[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan]-8-yl]carbonyl]phenyl]pyridineN-oxide

[0722]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0723]4-[2-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0724]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0725]4-[5-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0726]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0727]4-[5-[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0728]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0729]4-[2-[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0730]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-8-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0731]4-[5-[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0732]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-8-[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0733]4-[2-[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0734]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0735]4-[5-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0736]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0737]4-[5-[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0738]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-8-[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0739]4-[5-[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0740]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8[[6-(pyridin-4-yl)pyridazin-3-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0741]4-[6-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0742]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[[6(pyridin-4-yl)pyridazin-3-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0743]4-[6-[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0744]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-8-[[6-(pyridin-4-yl)pyridazin-3-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0745]4-[6-[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0746]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0747]4-[3-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0748]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-8[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0749]4-[6-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0750]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[[6(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0751]4-[3-[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0752]3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-8-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0753]4-[6-[3-[(5-Chloroindol-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0754]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-8-[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0755]4-[3-[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0756]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-8-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]-3,8-diazabicyclo[3.2.1]octane

[0757]4-[6-[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-6,7-dihydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0758]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0759]2-[2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0760]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2-(pyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0761]2-[5-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0762]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0763]2-[2-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0764]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[2-(pyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0765]2-[5-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0766]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0767]2-[2-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0768]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[2-(pyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0769]2-[5-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0770]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrazin-2-yl]carbonyl]piperazine

[0771]2-[5-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0772]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrazin-2-yl]carbonyl]piperazine

[0773]2-[5-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0774] 1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrazin-2-yl] carbonyl] piperazine

[0775]2-[5-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0776]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)pyridazin-3-yl]carbonyl]piperazine

[0777]2-[6-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0778]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)pyridazin-3-yl]carbonyl]piperazine

[0779]2-[6-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0780]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)pyridazin-3-yl]carbonyl]piperazine

[0781]2-[6-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0782]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0783]2-[3-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0784]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[3-(pyridin-2-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0785]2-[6-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0786]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0787]2-[3-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0788]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[3-(pyridin-2-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0789]2-[6-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0790]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0791]2-[3-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0792]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[3-(pyridin-2-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0793]2-[6-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0794]1-[[5-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[0795]2-(Aminomethyl)-6-[2-[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0796]1-[[2-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[0797]2-(Aminomethyl)-6-[5-[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0798]1-[[5-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[0799]2-(Aminomethyl)-6-[2-[4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0800]1-[[2-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[0801]2-(Aminomethyl)-6-[5-[4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0802]1-[[5-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[0803]2-(Aminomethyl)-6-[2-[4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0804]1-[[2-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[0805]2-(Aminomethyl)-6-[5-[4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0806]1-[(6-Chloronaphthalen-2-yl)sulfonyl)-4-[[5-(6-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0807]2-[2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-methylpyridineN-oxide

[0808]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2-(6-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0809]2-[5-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-methylpyridineN-oxide

[0810]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(6-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0811]2-[2-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-methylpyridineN-oxide

[0812]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[2-(6-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0813]2-[5-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-methylpyridineN-oxide

[0814]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(6-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0815]2-[2-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-methylpyridineN-oxide

[0816]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[2-(6-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0817]2-[5-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-methylpyridineN-oxide

[0818] 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[4-(4-methylpyridin-2-yl)phenyl]carbonyl]piperazine

[0819]2-[4-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-6-methylpyridineN-oxide

[0820] 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(4-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0821]2-[2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-4-methylpyridineN-oxide

[0822]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2-(4-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0823]2-[5-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-4-methylpyridineN-oxide

[0824]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(4-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0825]2-[2-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-4-methylpyridineN-oxide

[0826]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[2-(4-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0827]2-[5-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-4-methylpyridineN-oxide

[0828]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(4-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0829]2-[2-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-4-methylpyridineN-oxide

[0830]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[2-(4-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0831]2-[5-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-4-methylpyridineN-oxide

[0832]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]piperazine

[0833]2-[2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-(hydroxymethyl)pyridineN-oxide

[0834] 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]piperazine

[0835]2-[5-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-(hydroxymethyl)pyridineN-oxide

[0836]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]piperazine

[0837]2-[2-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-(hydroxymethyl)pyridineN-oxide

[0838]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[2-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]piperazine

[0839]2-[5-[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-(hydroxymethyl)pyridineN-oxide

[0840]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]piperazine

[0841]2-[2-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-(hydroxymethyl)pyridineN-oxide

[0842] 1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[2-[6(hydroxymethyl)pyridin-2-yl] pyrimidin-5-yl]carbonyl]piperazine

[0843]2-[5-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-(hydroxymethyl)pyridineN-oxide

[0844]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(pyridin-2-yl)phenyl]carbonyl]piperazine1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(pyridin-2-yl)phenyl]carbonyl]piperazine

[0845]2-[4-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0846]2-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0847]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0848]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0849]2-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0850]2-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0851]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(pyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0852]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(pyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0853]2-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0854]2-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0855]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrazin-2-yl]carbonyl]piperazine

[0856]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrazin-2-yl]carbonyl]piperazine

[0857]2-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0858]2-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0859]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)pyridazin-3-yl]carbonyl]piperazine

[0860]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)pyridazin-3-yl]carbonyl]piperazine

[0861]2-[6-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0862]2-[6-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0863]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0864]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0865]2-[3-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0866]2-[3-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0867] 1-[(5-Chlorobenzimidazo-2-yl)sulfonyl]-4-[[3-(pyridin-2-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0868]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[3-(pyridin-2-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0869]2-[6-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0870]2-[6-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0871]1-[[4-[6-(Aminomethyl)pyridin-2-yl]phenyl]carbonyl]-4[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0872]1-[[4-[6-(Aminomethyl)pyridin-2-yl]phenyl]carbonyl]-4[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0873]2-(Aminomethyl)-6-[4-[4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0874]2-(Aminomethyl)-6-[4-[4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0875]1-[[5-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]-4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0876]1-[[5-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]-4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0877]2-(Aminomethyl)-6-[2-[4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0878]2-(Aminomethyl)-6-[2-[4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0879]1-[[2-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]-4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0880]1-[[2-[6-(Aminomethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]-4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0881]2-(Aminomethyl)-6-[5-[4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl)carbonylpyrimidin-2-yl]pyridineN-oxide

[0882]2-(Aminomethyl)-6-[5-[4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0883]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(6-methylpyridin-2-yl)phenyl]carbonyl]piperazine

[0884]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(6-methylpyridin-2-yl)phenyl]carbonyl]piperazine

[0885]2-[4-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-6-methylpyridineN-oxide

[0886]2-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-6-methylpyridineN-oxide

[0887]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(6-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0888]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(6-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0889]2-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-methylpyridineN-oxide

[0890]2-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-methylpyridineN-oxide

[0891]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(6-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0892]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(6-methylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0893]2-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-methylpyridineN-oxide

[0894]2-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-methylpyridineN-oxide

[0895]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(4-methylpyridin-2-yl)phenyl]carbonyl]piperazine

[0896]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(4-methylpyridin-2-yl)phenyl]carbonyl]piperazine

[0897]2-[4-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-4-methylpyridineN-oxide

[0898]2-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-4-methylpyridineN-oxide

[0899]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(4-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0900]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(4-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[0901]2-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-4-methylpyridineN-oxide

[0902]2-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-4-methylpyridineN-oxide

[0903]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(4-dimethylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0904]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(4-dimethylpyridin-2-yl)pyrimidin-5-yl]carbonyl]piperazine

[0905]2-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-4-methylpyridineN-oxide

[0906]2-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-4-methylpyridineN-oxide

[0907]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-[6(hydroxymethyl)pyridin-2-yl]phenyl]carbonyl]piperazine

[0908]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-[6(hydroxymethyl)pyridin-2-yl]phenyl]carbonyl]piperazine

[0909]2-[4-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-6-(hydroxymethyl)pyridineN-oxide

[0910]2-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-6-(hydroxymethyl)pyridineN-oxide

[0911]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]piperazine

[0912]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-2-yl]carbonyl]piperazine

[0913]2-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-(hydroxymethyl)pyridineN-oxide

[0914]2-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-6-(hydroxymethyl)pyridineN-oxide

[0915]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]piperazine

[0916]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-[6(hydroxymethyl)pyridin-2-yl]pyrimidin-5-yl]carbonyl]piperazine

[0917]2-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-(hydroxymethyl)pyridineN-oxide

[0918]2-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-6-(hydroxymethyl)pyridineN-oxide

[0919]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(pyridin-4-yl)phenyl]carbonyl]piperazine1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(pyridin-4-yl)phenyl]carbonyl]piperazine

[0920]4-[4-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0921]4-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0922]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0923]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0924]4-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0925]4-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0926]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]piperazine

[0927]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]piperazine

[0928]4-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0929]4-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0930]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]piperazine

[0931]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]piperazine

[0932]4-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0933]4-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrazin-2-yl]pyridineN-oxide

[0934]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)pyridazin-3-yl]carbonyl]piperazine

[0935]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)pyridazin-3-yl]carbonyl]piperazine

[0936]4-[6-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0937]4-[6-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyridazin-3-yl]pyridineN-oxide

[0938]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0939]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazine

[0940]4-[3-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0941]4-[3-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-6-yl]pyridineN-oxide

[0942]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0943]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[0944]4-[6-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0945]4-[6-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl-1,2,4-triazin-3-yl]pyridineN-oxide

[0946]1-[[4-[2-(Aminomethyl)pyridin-4-yl]phenyl]carbonyl]-4[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0947]1-[[4-[2-(Aminomethyl)pyridin-4-yl]phenyl]carbonyl]-4[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0948]2-(Aminomethyl)-4-[4-[4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0949]2-(Aminomethyl)-4-[4-[4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]pyridineN-oxide

[0950]1-[[5-[2-(Aminomethyl)pyridin-4-yl]pyrimidin-2-yl]carbonyl]-4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0951]1-[[5-[2-(Aminomethyl)pyridin-4-yl]pyrimidin-2-yl]carbonyl]-4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0952]2-(Aminomethyl)-4-[2-[4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0953]2-(Aminomethyl)-4-[2-[4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[0954]1-[[2-[2-(Aminomethyl)pyridin-4-yl]pyrimidin-5-yl]carbonyl]-4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0955]1-[[2-[2-(Aminomethyl)pyridin-4-yl]pyrimidin-5-yl]carbonyl]-4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazine

[0956]2-(Aminomethyl)-4-[5-[4-[(5-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0957]2-(Aminomethyl)-4-[5-[4-[(6-chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]pyridineN-oxide

[0958]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(2-methylpyridin-4-yl)phenyl]carbonyl]piperazine

[0959]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-(2-methylpyridin-4-yl)phenyl]carbonyl]piperazine

[0960]4-[4-[4-[(S-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-2-methylpyridineN-oxide

[0961]4-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-2-methylpyridineN-oxide

[0962]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0963]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[0964]4-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-2-methylpyridineN-oxide

[0965]4-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-2-methylpyridineN-oxide

[0966]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(2-methylpyridin-4-yl)pyrimidin-5-yl]carbonyl]piperazine

[0967]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-(2-methylpyridin-4-yl)pyrimidin-5-yl]carbonyl]piperazine

[0968]4-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-2-methylpyridineN-oxide

[0969]4-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-2-methylpyridineN-oxide

[0970]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[4-[2-(hydroxymethyl)pyridin-4-yl]phenyl]carbonyl]piperazine

[0971]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[([4-[2-(hydroxymethyl)pyridin-4-yl]phenyl]carbonyl]piperazine

[0972]4-[4-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-2-(hydroxymethyl)pyridineN-oxide

[0973]4-[4-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylphenyl]-2-(hydroxymethyl)pyridineN-oxide

[0974]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-[2-(hydroxymethyl)pyridin-4-yl]pyrimidin-2-yl]carbonyl]piperazine

[0975]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[5-[2-(hydroxymethyl)pyridin-4-yl]pyrimidin-2-yl]carbonyl]piperazine

[0976]4-[2-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-2-(hydroxymethyl)pyridineN-oxide

[0977]4-[2-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-5-yl]-2-(hydroxymethyl)pyridineN-oxide

[0978]1-[(5-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-[2-(hydroxymethyl)pyridin-4-yl]pyrimidin-5-yl]carbonyl]piperazine

[0979]1-[(6-Chlorobenzimidazol-2-yl)sulfonyl]-4-[[2-[2-(hydroxymethyl)pyridin-4-yl]pyrimidin-5-yl]carbonyl]piperazine

[0980]4-[5-[4-[(5-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-2-(hydroxymethyl)pyridineN-oxide

[0981]4-[5-[4-[(6-Chlorobenzimidazol-2-yl)sulfonyl]piperazin-1-yl]carbonylpyrimidin-2-yl]-2-(hydroxymethyl)pyridineN-oxide

[0982]1-[(5-Chloroisoindolin-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine4-[4-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[0983]1-[(5-Chloroisoindolin-2-yl)sulfonyl]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[0984]4-[4-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[0985]1-[(5-Chloro-1-isoindolinon-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[0986]4-[4-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[0987]1-[(5-Chloro-2-isoindolinon-2-yl)sulfonyl]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[0988]4-[4-[[4-[(5-Chloro-2-isoindolinon-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[0989]1-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[0990]4-[4-[[4-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[0991]1-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)]-4-[4(2-methylpyridin-4-yl)benzoyl]piperazine

[0992]4-[4-[[4-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[0993]1-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[0994]4-[4-[[4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[0995]1-[(5-Chloro-3-hydroxyindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[0996]4-[4-[[4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[0997]1-[(5-Chloro-3-methoxyindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[0998]4-[4-[[4-[(5-Chloro-3-methoxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[0999]1-[(5-Chloro-3-methoxyindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[1000]4-[4-[[4-[(5-Chloro-3-methoxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[1001]1-[(3-Acetoxy-5-Chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[1002]4-[4-[[4-[(3-Acetoxy-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[1003]1-[(3-Acetoxy-5-chloroindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[1004]4-[4-[[4-[(3-Acetoxy-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[1005]1-[(5-Chloro-3-hydroxymethylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[1006]4-[4-[[4-[(5-Chloro-3-hydroxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[1007]1-[(5-Chloro-3-hydroxymethylindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[1008]4-[4-[[4-[(5-Chloro-3-hydroxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[1009]1-[(5-Chloro-3-methoxymethylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[1010]4-[4-[[4-[(5-Chloro-3-methoxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[1011]1-[(5-Chloro-3-methoxymethylindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[1012]4-[4-[[4-[(5-Chloro-3-methoxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[1013]1-[(1-Acetyl-5-chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[1014]4-[4-[[4-[(1-Acetyl-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[1015]1-[(1-Acetyl-5-chloroindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[1016]4-[4-[[4-[(1-Acetyl-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[1017]1-[(5-Chloro-1-formylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[1018]4-[4-[[4-[(5-Chloro-1-formylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[1019]1-[(5-Chloro-1-formylindol-2-yl)]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[1020]4-[4-[[4-[(5-Chloro-1-formylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide

[1021]1-[(5-Chloroisoindolin-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1022]4-[2-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1023]1-[(5-Chloroisoindolin-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1024]4-[2-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1025]1-[(5-Chloro-1-isoindolinon-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1026]4-[2-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1027]1-[(5-Chloro-2-isoindolinon-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1028]4-[2-[[4-[(5-Chloro-2-isoindolinon-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1029]1-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1030]4-[2-[[4-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1031]1-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)]-4-[[5(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1032]4-[2-[[4-[(1,2,3,4-Tetrahydro-5-chloroisoquinolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1033]1-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1034]4-[2-[[4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1035]1-[(5-Chloro-3-hydroxyindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1036]4-[2-[[4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1037]1-[(5-Chloro-3-methoxyindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1038] 4-[2-[[4-[(5-Chloro-3-methoxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridine N-oxide

[1039]1-[(5-Chloro-3-methoxyindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1040]4-[2-[[4-[(5-Chloro-3-methoxyindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1041]1-[(3-Acetoxy-5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1042]4-[2-[[4-[(3-Acetoxy-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1043]1-[(3-Acetoxy-5-chloroindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1044]4-[2-[[4-[(3-Acetoxy-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1045]1-[(5-Chloro-3-hydroxymethylindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1046]4-[2-[[4-[(S-Chloro-3-hydroxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1047]1-[(5-Chloro-3-hydroxymethylindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1048]4-[2-[[4-[(5-Chloro-3-hydroxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1049]1-[(5-Chloro-3-methoxymethylindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1050]4-[2-[[4-[(5-Chloro-3-methoxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1051]1-[(5-Chloro-3-methoxymethylindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1052]4-[2-[[4-[(5-Chloro-3-methoxymethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1053]1-[(1-Acetyl-5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1054]4-[2-[[4-[(1-Acetyl-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1055]1-[(1-Acetyl-5-chloroindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1056]4-[2-[[4-[(1-Acetyl-5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1057]1-[(5-Chloro-1-formylindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1058]4-[2-[[4-[(5-Chloro-1-formylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-oxide

[1059]1-[(5-Chloro-1-formylindol-2-yl)]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carboxy]piperazine

[1060]4-[2-[[4-[(5-Chloro-1-formylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-oxide

[1061]2,6-Bis[(N-methylcarbamoyl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1062]2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1063]2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1064]2,6-Bis(hydroxyethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1065]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1066]2,6-Bis[(N-methylcarbamoyl)methyl]-4-[(4-chloro-2-hydroxystyryl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1067]2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(4-chloro-2-hydroxystyryl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1068] 2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-[(4-chloro-2-hydroxystyryl)sulfonyl]-1-[5-(pyridin-4-yl) pyrimidin-2-yl]piperazine

[1069]2,6-Bis(hydroxyethyl)-4-[(4-chloro-2-hydroxystyryl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1070]2,6-Bis[(N-methylcarbamoyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1071]2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1072]2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1073]2,6-Bis(hydroxyethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1074]2,6-Bis[(N-methylcarbamoyl)methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1075]2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1076]2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1077]2,6-Bis(hydroxyethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1078]4-[5-[[2,6-Bis(carbamoylmethyl)-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1079]4-[5-[[2,6-Bis[(N-methylcarbamoyl)methyl]-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1080]4-[5-[[2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1081]4-[5-[[2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1082]4-[5-[[2,6-Bis(hydroxyethyl)-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1083]4-[5-[[4-[(4-Chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1084]4-[5-[[2,6-Bis(carbamoylmethyl)-4-[(4-chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1085]4-[5-[[2,6-Bis[(N-methylcarbamoyl)methyl]-4-[(4-chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1086]4-[5-[[2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(4-chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1087]4-[5-[[2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-[(4-chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1088]4-[5-[[2,6-Bis(hydroxyethyl)-4-[(4-chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1089]4-[5-[[2,6-Bis(carbamoylmethyl)-4-(5-chloroindol-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1090]4-[5-[[2,6-Bis[(N-methylcarbamoyl)methyl]-4-(5-chloroindol-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1091]4-[5-[[2,6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-(5-chloroindol-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1092]4-[5-[[2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-(5-chloroindol-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1093]4-[5-[[2,6-Bis(hydroxyethyl)-4-(5-chloroindol-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1094]4-[5-[[2,6-Bis(carbamoylmethyl)-4-(6-chlorobenzo[b]thien-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-ylpyridine N-oxide

[1095]4-[5-[[2,6-Bis[(N-methylcarbamoyl)methyl]-4-(6-chlorobenzo[b]thien-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridine N-oxide

[1096]4-[5-[[2,6-bis[(N,N-dimethylcarbamoyl)methyl]-4-(6-chlorobenzo[b]thien-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1097]4-[5-[[2,6-Bis[(morpholin-4-yl)carbonylmethyl]-4-(6-chlorobenzo[b]thien-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1098]4-[5-[[2,6-Bis(hydroxyethyl)-4-(6-chlorobenzo[b]thien-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[1099]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[5-(2-hydroxymethylpyridin-4-yl)pyrimidin-2-yl]piperazine

[1100]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[5-(2-dimethylaminomethylpyridin-4-yl)pyrimidin-2-yl]piperazine

[1101]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[5-(2-carbamoylpyridin-4-yl)pyrimidin-2-yl]piperazine

[1102]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine

[1103]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[4-(2-dimethylaminomethylpyridin-4-yl)benzoyl]piperazine

[1104]1-[(4-Chloro-2-hydroxystyryl)sulfonyl]-4-[4-(2-carbamoylpyridin-4-yl)benzoyl]piperazine

[1105]4-[(6-Chloronaphthalene-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1106]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1107]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1108]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-hydroxyethyl-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[1109]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-hydroxy-9-[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1110]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-hydroxy3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1111]3-[(5-Chloroindol-2-yl)sulfonyl]-7-hydroxy-9-[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1112]4-[4-[[[3-[(5-Chloroindol-2-yl)sulfonyl]-7-hydroxy-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1113]3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-7-hydroxy-9-[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane4-[4-[[[3-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-7-hydroxy-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1114]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-hydroxy-9-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]-3,9-diazabicyclo[3.3.1]nonane

[1115]4-[2-[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-hydroxy-3,9-diazabicyclo[3.3.1]nonan-8-yl]carbonylpyrimidin-5-yl]pyridineN-oxide

[1116]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-methylamino-9[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1117]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-methylamino-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1118]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-dimethylamino-9[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1119]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-dimethylamino-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1120]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-piperidino-9-[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1121]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-piperidino-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1122]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-morpholino-9-[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1123]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-morpholino-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1124]3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-(4-methylpiperazin-1-yl)-9-[4-(pyridin-4-yl)benzoyl]-3,9-diazabicyclo[3.3.1]nonane

[1125]4-[4-[[[3-[(6-Chloronaphthalen-2-yl)sulfonyl]-7-(4-methylpiperazin-1-yl)-3,9-diazabicyclo[3.3.1]nonan]-9-yl]carbonyl]phenyl]pyridineN-oxide

[1126]1-[[(6RS)-6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1127]1-[[(6RS)-6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1128]1-[[(2RS)-6-Aminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1129]1-[[(2RS)-6-Aminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1130]1-[(7-Aminomethylnaphthalen-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1131]1-[(7-Aminomethylnaphthalen-2-yl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1132]1-[(6-Aminomethylnaphthalen-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1133]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(isoquinolin-7-yl)carbonyl]piperazine

[1134]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(quinolyl-2-yl)carbonyl]piperazine

[1135]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4-hydroxyquinolin-2-yl)carbonyl]piperazine

[1136]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(8-hydroxyquinolin-7-yl)carbonyl]piperazine

[1137]1-[(Benzimidazol-5-yl)carbonyl]-4-[(6-chloronaphthalen2-yl)sulfonyl]piperazine

[1138]1-[(Benzimidazol-5-yl)carbonyl]-4-[(6-chloronaphthalen2-yl)sulfonyl]homopiperazine

[1139]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1140]1-[(E)-4-Chlorostyrylsulfonyl]-4-[(thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1141]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]piperazine

[1142]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[trans-3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propenoyl]piperazine

[1143]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propionyl]piperazine

[1144]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propyl]piperazine

[1145]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[N-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]carbamoyl]piperazine

[1146]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1147]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl]-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1148]2-Carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1149]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1150]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[N-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]piperazine

[1151]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[N-methy-N-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]piperazine

[1152]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(1-pyrrolin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]carbonyl]piperazine

[1153]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1154]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1155]1-[(6-Carbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[1156]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(1-pyrrolin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[1157]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-formyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1158]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1159]2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridiniumiodide

[1160]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-N-oxide

[1161]2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1162]2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1163]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[1164]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[1165]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-3-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[1166]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[1167]1-[(E)-4-Chlorostyrylsulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1168]1-[(E)-4-Chlorostyrylsulfonyl]-4-[6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1169](3S)-3-[(6-Chloronaphthalen-2-yl)sulfonamide]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]pyrrolidine

[1170](3S)-3-[(6-Chloronaphthalen-2-yl)sulfonamide]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]pyrrolidine

[1171](3S)-1-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]amino]pyrrolidine

[1172](3S)-3-[(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)carbonylamino]-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine

[1173]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]homopiperazine

[1174]4-[(6-Chloronaphthalen-2-yl)sulfonamide]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperidine

[1175]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethylbenzofuran-2-yl)carbonyl]piperazine

[1176]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-aminohydroxyiminomethylbenzothiophen-2-yl)carbonyl]piperazine

[1177]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazine

[1178]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(2-methyl1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazine

[1179]6-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniumiodide

[1180]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1181]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1182]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)carbonyl]piperazine

[1183]1-[(5-Chlorobenzo[b]furan-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1184]1-[(6-Chlorobenzo[b]furan-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1185]1-[(5-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1186]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1187]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5,6,7,8-tetrahydro-1,6-naphthylidin-2-yl)carbonyl]piperazine

[1188]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthylidin-2-yl)carbonyl]piperazine

[1189]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1190]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1191]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1192]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1193]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(1,5-dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1194]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrofro[2,3-c]pyridin-2-yl)carbonyl]piperazine

[1195]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(3-hydroxy-6-methyl-4,5,6,7-tetrahydrofro [2,3-c]pyridin-2-yl)carbonyl]piperazine

[1196]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-methyl-3-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)carbonyl]piperazine

[1197]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydroxazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[1198]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1199]2,6-Bis(carbamoylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1200]cis-2,6-Bis(carbamoylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1201]4-[(5-Chloroisoindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1202]2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1203]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1204]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazineN-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]glycineethyl ester

[1205]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-(morpholin-4-yl)carbamoyl]piperazine

[1206] EthylN′-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]hydrazinoacetate

[1207]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[[(morpholin-4-yl)carbonyl]methyl]carbamoyl]piperazine

[1208]4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]morpholine

[1209]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1210] Methyl[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetate

[1211]2-[[N-(tert-Butoxy)amino]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1212][4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetamide

[1213]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-isopropyl)carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1214]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[(piperidin-1-yl)carbonyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1215]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxybenzyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1216]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1217]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1218]N′-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]hydrazinoaceticacid

[1219]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[N-(tetrahydropyran-2-yloxy)]carbamoyl]piperazine

[1220]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-hydroxamicacid

[1221]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-hydroxybenzyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1222]1-[(6-Bromonaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1223]1-[(7-Amidinonaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1224]1-[(6-Amidinonaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1225]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[7-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1226]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1227]1-[(7-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1228]1-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1229]1-[(6-Ethynylnaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1230]1-[(5-Bromoindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1231]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1232]1-[(5-Amidinoindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1233]1-[(6-Amidinoindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1234]1-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1235]1-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1236]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]piperazine

[1237]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1238]1-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1239]1-[(6-Amidinobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1240]1-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1241]1-[[6-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1242]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1243]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1244]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1245]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1246]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1247]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-lyl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1248]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1249]2-[[4-[(5-Bromoindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1250]2-[[4-[(5-Ethynylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1251]2-[[2-(Carbamoyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1252]2-[[2-(Carbamoylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1253]2-[[2,6-Bis(carbamoylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1254]2-[[2-[[(Tetrazol-5-ylmethyl)amino]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1255]2-[[2-[2-(Tetrazol-5-yl)ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1256]2-[[2-[(Morpholin-4-ylcarbonyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1257]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(carbamoylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1258]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1259]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(tetrazol-5-yl)amino]carbonyl]piperazine

[1260]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(tetrazol-5-ylmethyl)amino]carbonyl]piperazine

[1261]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(tetrazol-5-ylamino)carbonyl]methyl]piperazine

[1262]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[[(tetrazol-5-ylmethyl)amino]carbonyl]methyl]piperazine

[1263]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(tetrazol-5-ylmethyl)piperazine

[1264]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2(tetrazol-5-yl)ethyl]piperazine

[1265]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(morpholin-4-ylcarbonyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1266]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[(morpholin-4-ylcarbonyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1267]4-[(5-Ethynylisoindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1268]4-[(5-Chloroisoindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1269]2-(Carbamoylmethyl)-4-[(5-chloroisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1270]2-(Carbamoylmethyl)-4-[(5-ethynylisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1271]4-[(5-Chloroisoindol-2-yl)sulfonyl]-2-(N-methylcarbamoylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1272]4-[(5-Chloroisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N,N-dimethylcarbamoylmethyl)piperazine

[1273]4-[(5-Chloroisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1274]4-[(5-Bromoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(morpholinocarbonylmethyl)piperazine

[1275]4-[(5-Ethynylisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1276]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydroxazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[1277]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1278]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoylmethyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1279]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(morpholinocarbonylmethyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1280]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(morpholinocarbonylmethyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1281]4-[(5-Bromoindol-2-yl)sulfonyl]-2-(morpholinocarbonylmethyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1282]2,6-Bis(carbamoylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1283]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1284]2,6-Bis(carbamoylmethyl)-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1285]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[(ethoxycarbonylmethyl)aminocarbonyl]methyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1286]4-[(5-Chloroindol-2-yl)sulfonyl]-2[[(ethoxycarbonylmethyl)aminocarbonyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1287]4-[(5-Chloroindol-2-yl)sulfonyl]-2[[(carboxymethyl)aminocarbonyl]methyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1288]4-[(5-Chloroindol-2-yl)sulfonyl]-2[[(carboxymethyl)aminocarbonyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1289]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[[(tetrazol-5-yl)methyl]aminocarbonyl]methyl]piperazine

[1290]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[[(tetrazol-5-yl)methyl]aminocarbonyl]methyl]piperazine

[1291]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1292]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1293]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1294]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2(tetrazol-5-yl)ethyl]piperazine

[1295]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(2-oxopyrrolidin-1-yl)methyl]piperazine

[1296]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(2-oxopyrrolidin-1-yl)methyl]piperazine

[1297]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxopyrrolidin-1-yl)ethyl]piperazine

[1298]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxopyrrolidin-1-yl)ethyl]piperazine

[1299]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(4-hydroxy-2-oxopyrrolidin-1-yl)methyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1300]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(4-hydroxy-2-oxopyrrolidin-1-yl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1301]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(4-hydroxy-2-oxopyrrolidin-1-yl)ethyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1302]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(4-hydroxy-2-oxopyrrolidin-1-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1303]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(2,5-dioxopyrrolidin-1-yl)methyl]piperazine

[1304]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(2,5-dioxopyrrolidin-1-yl)methyl]piperazine

[1305]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2,5-dioxopyrrolidin-1-yl)ethyl]piperazine

[1306]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2,5-dioxopyrrolidin-1-yl)ethyl]piperazine

[1307]2,6-Bis[2-(4-hydroxy-2-oxopyrrolidin-1-yl)ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1308]2,6-Bis[2-(2-oxopyrrolidin-1-yl)ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1309]2,6-Bis[2-(tetrazol-5-yl)ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1310]2,6-Bis[(tetrazol-5-yl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1311]2,6-Bis((N-methylcarbamoyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1312]2,6-Bis[(2,5-dioxopyrrolidin-1-yl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1313]2,6-Bis[2-(2,5-dioxopyrrolidin-1-yl)ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1314]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1315]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1316]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[7-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1317]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1318]4-[(7-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1319]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1320]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1321] 2-carboxylic acid

[1322]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1323] 2-carboxylic acid

[1324]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1325]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1326]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1327]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1328]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1329]4-[(6-amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1330]1-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1331]4-[[6-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1332]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1333]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-(N-methoxycarbonylamidino)benzo[b]thien-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1334]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1335]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid

[1336]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]piperazine-2-carboxylicacid

[1337]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1338]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1339]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[7-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1340]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1341] 4-[(7-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1342] 4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1343]4-[(5-Amidinoindol-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1344]4-[(6-Amidinoindol-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1345]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1346]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1347]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1348]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1349]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1350]4-[(6-Amidinobenzo[b]thien-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1351]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1352]4-[[6-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1353]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1354]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1355]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1356]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1357]2-(Ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]piperazine

[1358]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1359]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1360]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1361]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1362]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1363]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1364]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1365]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1366]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1367]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1368]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1369]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1370]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1371]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]-2[(tetrazol-5-yl)methyl]piperazine

[1372]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1373]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1374]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(tetrazol-5-yl)methyl]piperazine

[1375]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(tetrazol-5-yl)methyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1376]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(tetrazol-5-yl)methyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1377]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1378]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1379]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1380]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1381]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2(tetrazol-5-yl)ethyl]piperazine

[1382]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2(tetrazol-5-yl)ethyl]piperazine

[1383]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2(tetrazol-5-yl)ethyl]piperazine

[1384]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1385]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1386]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1387]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1388]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1389]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1390]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1391]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1392]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1393]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1394]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1395]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1396]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1397]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1398]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1399]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1400]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1401]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1402]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1403]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1404]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1405]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1406]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1407]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1408]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1409]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]-2-[N[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1410]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1411]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1412]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoyl]piperazine

[1413]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[N[(tetrazol-5-yl)methyl]carbamoyl]piperazin-1-yl]carbonyl]6-methylthiazolo[5,4-c]pyridiniumiodide

[1414] 2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-[N-[(tetrazol-55yl)methyl]carbamoyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1415]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1416]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1417]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1418]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1419]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1420]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1421]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1422]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1423]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1424]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1425]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1426]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1427]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1428] 1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1429]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1430]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1431]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazine

[1432]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[N[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1433]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-[N-[(tetrazol-5-yl)methyl]carbamoylmethyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1434]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1435]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1436]2-(Ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1437]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1438]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1439]4-[(5-Amidinoindol-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1440]4-[(6-Amidinoindol-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1441]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1442]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1443]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(ethoxycarbonylmethyl)-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]piperazine

[1444]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(ethoxycarbonylmethyl)-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1445]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1446]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1447]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(ethoxycarbonylmethyl)-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sylfonyl]piperazine

[1448]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1449]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-2-(ethoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1450]2-(Ethoxycarbonylmethyl)-4-[[5-[N-(methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1451]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1452]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-(ethoxycarbonylmethyl)piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1453]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1454]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1455]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazin-2-aceticacid

[1456]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1457]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1458]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1459]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1460]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1461]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1462]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]piperazin-2-aceticacid

[1463]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazin-2-aceticacid

[1464]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazin-2-aceticacid

[1465]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1466]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazin-2-aceticacid

[1467]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1468]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1469]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-aceticacid

[1470]2-[[2-(Carboxymethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1471]2-[[2-(Carboxymethyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1472]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1473]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1474]2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1475]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1476]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1477]4-[(5-Amidinoindol-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1478]4-[(6-Amidinoindol-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1479]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1480]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1481]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(N-methylcarbamoyl)methyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]piperazine

[1482]2-[(N-Methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1483]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1484]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1485]2-[(N-Methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1486]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1487]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1488]2-[(N-methylcarbamoyl)methyl]-4-[[5-[N-(methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1489]2-[[2-[(N-Methylcarbamoyl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1490]2-[[2-[(N-methylcarbamoyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1491]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1492]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1493]2-[[N-(Ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen2-yl]sulfonyl]piperazine

[1494]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1495]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1496]4-[(5-Amidinoindol-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1497]4-[(6-Amidinoindol-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1498]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1499]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1500]2-[[N-(Ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]piperazine

[1501]2-[[N-(Ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1502]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1503]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1504]2-[[N-(Ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1505]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1506]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1507]2-[[N-(Ethoxycarbonylmethyl)carbamoyl]methyl]-4-[[5-[N-(methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1508]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(ethoxycarbonylmethyl)carbamoyl]methyl]piperazin-1yl]carbonyl]-6-methylthiazolo[5,4-c]pyridinium iodide

[1509]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1510]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1511]2-[[N-(Carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]piperazine

[1512]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1513]2-[[N-(Carboxymethyl)carbamoyl]methyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1514]4-[(5-Amidinoindol-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1515]4-[(6-Amidinoindol-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1516]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1517]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1518]2-[[N-(Carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]piperazine

[1519]2-[[N-(Carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-cpyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]piperazine

[1520]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1521]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1522] 2-[[N—(Carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]piperazine

[1523]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1524]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-2-[[N-(carboxymethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1525]2-[[N-(Carboxymethyl)carbamoyl]methyl]-4-[[5-[N-(methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1526]2-[[2-[[N-(Carboxymethyl)carbamoyl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1527]2-[[2-[[N-(Carboxymethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1528]4-[(7-Amidinonaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1529]4-[(6-Amidinonaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1530]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]naphthalen-2-yl]sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1531]4-[(6-[(Amino)(hydroxyimino)methyl]naphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1532]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1533]4-[(5-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1534]4-[(6-Amidinoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1535]4-[[5-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1536]4-[[6-[(Amino)(hydroxyimino)methyl]indol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1537]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(N-methoxycarbonylamidino)indol-2-yl]sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1538]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[6-[N-(methoxycarbonyl)amidino]indol-2-yl]sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1539]4-[(5-Amidinobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1540]4-[[5-[(Amino)(hydroxyimino)methyl]benzo[b]thien-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1541]1-[(6-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-[N-(methoxycarbonyl)amidino]benzo[b]thien-2-yl]sulfonyl]-2[(morpholin-0.4-yl)carbonylmethyl]piperazine

[1542]4-[(5-Amidinoisoindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1543]4-[[5-[(Amino)(hydroxyimino)methyl]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl] piperazine

[1544]4-[[5-[N-(Methoxycarbonyl)amidino]isoindol-2-yl]sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1545]2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1546]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumiodide

[1547]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(7-cyano-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2,5-dioxopyrrolidin-1-yl)ethyl]piperazine

[1548]1-[(7-Carbamoyl-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]2-[2-(2,5-dioxopyrrolidin-1-yl)ethyl]piperazine

[1549]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(7-dimethylamino-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2,5-dioxopyrrolidin-lyl)ethyl]piperazine

[1550]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(7-cyano-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1551]1-[(7-Carbamoyl-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]2-[2-(tetrazol-5-yl)ethyl]piperazine

[1552]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(7-dimethylamino-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(tetrazol-5-yl)ethyl]piperazine

[1553]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(7-cyano-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[[[(ethoxycarbonyl)methyl]amino]carbonyl]methyl]piperazine

[1554]1-[(7-Carbamoyl-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]2[[[[(ethoxycarbonyl)methyl]amino]carbonyl]methyl]piperazine

[1555]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(7-dimethylamino-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2[[[[(ethoxycarbonyl)methyl]amino]carbonyl]methyl]piperazine

[1556]2-[[[(Carboxymethyl)amino]carbonyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(7-cyano-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1557]1-[(7-Carbamoyl-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[[(carboxymethyl)amino]carbonyl]methyl]-4-[(5-chloroindol2-yl)sulfonyl]piperazine

[1558]2-[[[(Carboxymethyl)amino]carbonyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(7-dimethylamino-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1559]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[7[(dimethylamino)methyl]benzothiazol-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1560]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[7-[(dimethylaminomethyl)methyl]thiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1561]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[7-[(dimethylamino)methyl]-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1562]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[7-[(morpholin-4-yl)methyl]benzothiazol-2-yl)carbonyl]piperazine

[1563]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[6-(morpholin-4-yl)-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1564]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[7-(piperidin-1-yl)benzothiazol-2-yl)carbonyl]piperazine

[1565]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[6-(piperidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1566]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(2-methyl4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]piperazine

[1567]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-yl)carbonyl]piperazine

[1568]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(2-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1569]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1570]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methoxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazineA-[(6-Chlorohenzo[b]thien-2-yl)sulfonyl]-2-[(morpholin-4-ylcarbonyl)methyl]-1-[(6-sulfo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1571]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-sulfo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1572]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1573]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1574]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1575]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1576]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1577]1-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazinedimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1578]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine

[1579]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1580]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1581]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1582]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1583]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1584]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1585]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1586]2-[(N,N-Dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine

[1587]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1588]2-(2-Cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1589]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1590]2-(2-Cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1591]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1592]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1593]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1594]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1595]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1596]1-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1597]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1598]2-(2-Cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1599]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1600]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1601]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1602]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1603]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1604]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1605]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1606]1-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1607]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1608]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine

[1609]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1610]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1611]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1612]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1613]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1614]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1615]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1616]2-[(N,N-Dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine

[1617]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1618]2-(2-Cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1619]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1620]2-(2-Cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1621]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1622]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1623]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1624]4-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1625]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1626]1-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1627]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1628]2-(2-Cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1629]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1630]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1631]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(5,6-dihydrobenzo[f]isoquinolin-8-yl)carbonyl]piperazine

[1632]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(5,6-dihydropyrido[4,3-f]quinazolin-3-yl)carbonyl]piperazine

[1633]8-[[1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-5,6-dihydrobenzo[f]isoquinolineN-oxide

[1634]3-[[1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-5,6-dihydropyrido[4,3-f]quinazolineN-oxide

[1635]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1636]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1637]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(morpholin-4-ylcarbonylmethyl)piperazine

[1638]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1639]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[1640]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methanesulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1641]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methanesulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1642]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methanesulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(morpholin-4-ylcarbonylmethyl)piperazine

[1643]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methanesulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1644]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1645]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1646]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(2-dimethylamino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1647]4-[(6-Chlorobenzo[b]thiophen-2-yl)sulfonyl]-1-[(6-methyl-5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1648]4-[(6-Chlorobenzo[b]thiophen-2-yl)sulfonyl]-1-[(6-methyl-5-oxo-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1649]4-[(6-Chlorobenzo[b]thiophen-2-yl)sulfonyl]-1-[(5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1650]4-[(6-Chlorobenzo[b]thiophen-2-yl)sulfonyl]-1-[(5-oxo-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1651]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1652]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1653]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1654]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1655]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine.

[1656]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine.

[1657]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)piperazine.

[1658]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine.

[1659]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]piperazine.

[1660]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-4-[(6-ethynylbenzo[b]thien-2-yl)sulfonyl]piperazine.

[1661]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(2-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]piperazine

[1662]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-yl)carbonyl]piperazine

[1663]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(2-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1664]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1665]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(2-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]piperazine

[1666]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]piperazine

[1667]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(2-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-5-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1668]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1669]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methoxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1670]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methoxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1671]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(morpholin-4-ylcarbonyl)methyl]-1-[(6-sulfo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1672]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-sulfo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1673]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[(morpholin-4-ylcarbonyl)methyl]-1-[(6-sulfo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-piperazine

[1674]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-sulfo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1675]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1676]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1677]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(5,6-dimethyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1678]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1679]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1680]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1681]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1682]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1683]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1684]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1685]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(5,6-dimethyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]2-(N-methylcarbamoyl)piperazine

[1686]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1687]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1688]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1689]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1690]2-[(N,N-Dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1691]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1692]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1693]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1694]2-(2-Cyanoethyl)-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1695]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1696]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1697]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1698]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1699]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1700]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1701]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1702]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1703]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1704]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1705]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1706]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1707]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1708]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-2[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1709]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine.

[1710]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine.

[1711]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)piperazine.

[1712]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine.

[1713]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]piperazine.

[1714]1-[(6-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine.

[1715]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1716]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1717]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1718]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[1719]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1720]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1721]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1722]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1723]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1724]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1725]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(5,6-dimethyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1726]1-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[1727]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1728]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1729]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1730]2-[(N,N-Dimethylcarbamoyl)methyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1731]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1732]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine.

[1733]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]piperazine

[1734]2-(2-Cyanoethyl)-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridazin-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1735]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1736]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[1737]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1738]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine.

[1739]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1740]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1741]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1742]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1743]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1744]2-[(N,N-Dimethylcarbamoyl)methyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine.

[1745]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5,6-dihydrobenzo[f]isoquinolin-8-yl)carbonyl]piperazine

[1746]1-[(5,6-Dihydrobenzo[f]isoquinolin-8-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1747]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5,6-dihydropyrido[4,3-f]quinazolin-3-yl)carbonyl]piperazine

[1748]1-[(5,6-Dihydropyrido[4,3-f]quinazolin-3-yl)carbonyl]-4[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1749]8-[[1-[(5-Chloroindol-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-5,6-dihydrobenzo[f]isoquinolineN-oxide

[1750]8-[[1-[(5-Ethynylindol-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-5,6-dihydrobenzo[f]isoquinolineN-oxide

[1751]3-[[1-[(5-Chloroindol-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-5,6-dihydropyrido[4,3-f]quinazolineN-oxide

[1752]3-[[1-[(5-Ethynylindol-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-5,6-dihydropyrido[4,3-f]quinazolineN-oxide

[1753]1-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[1754]1-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[1755]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1756]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-hydroxyimino4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1757]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1758]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-ethylenedioxy4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1759]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]furan-2-yl)carbonyl]piperazine

[1760]1-[(6-Acetoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[1761]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1762]1-[(6-Amino-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[1763]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-dimethylamino-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1764]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[[6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbonyl]piperazine

[1765]1-[(6-Acetylamino-1-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[1766]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1767]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-hydroxyimino-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1768]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1769]1-[(6-Ethylenedioxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1770]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]furan-2-yl)carbonyl]piperazine

[1771]1-[(6-Acetoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1772]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]piperazine

[1773]1-[(6-Amino-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1774]1-[(6-Dimethylamino-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1775]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[[6-(pyrrolidin-1-yl)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbonyl]piperazine

[1776]1-[(6-Acetylamino-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1777]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1778]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-5-oxo-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[1779]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(morpholin-4-yl)carbonylmethyl]-1-[(5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1780]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(morpholin-41)carbonylmethyl]-1-[(5-oxo-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1781]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1782]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1783]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(thieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1784]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thieno[3,2-b]pyridineN-oxide

[1785]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1786]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1787]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(thieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1788]2-[[4-[(5-Ethynylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thieno[3,2-b]pyridineN-oxide

[1789]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1790]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1791]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1[(thieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1792]2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)piperazin-1-yl]carbonyl]thieno[3,2-b]pyridineN-oxide

[1793]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1[(4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1794]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(4-methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1795]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(thieno[3,2-b]pyridin-2-yl)carbonyl]piperazine

[1796]2-[[4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(cyanoethyl)piperazin-1-yl]carbonyl]thieno[3,2-b]pyridineN-oxide

[1797]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1798]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1799]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1800]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1801]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(2-dimethylamino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)carbonyl]piperazine

[1802]1-[(2-Dimethylamino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)carbonyl]-4-[(5-ethynylindol-2-yl)sulfonyl]piperazine

[1803]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1804]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1805]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(morpholin-4-ylcarbonylmethyl)piperazine

[1806]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-[((6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1807]1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methylsulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1808]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N-methylcarbamoyl)piperazine

[1809]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(morpholin-4-ylcarbonylmethyl)piperazine

[1810]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1811]1-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methylsulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1812]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1813]4-[(5-thynylindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(morpholin-4-ylcarbonylmethyl)piperazine

[1814]2-(2-Cyanoethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1[(6-methylsulfonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1815]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxopyridin-1-yl)ethyl]piperazine

[1816]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo-1,3-oxazolan-3-yl)ethyl]piperazine

[1817]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2[2-(2-oxopyridin-1-yl)ethyl]piperazine

[1818]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-[(coumarin-7-yl)oxy]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1819]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-[(coumarin-7-yl)oxy]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1820]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-[(cyclopropylcarbonyl)amino]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1821]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-[(cyclopropylcarbonyl)amino]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1822]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(cyclopropylcarbonyl)amino]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1823]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(cyclopropylcarbonyl)amino]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1824]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1825]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1826]4-[((6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-cyanomethyl-N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1827]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-cyanomethyl-N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1828]2-(3-Butynyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1829]2-(1-Butynyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1830]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1831]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1832]2-[[N,N-Bis(2-hydroxyethyl)carbamoyl]methyl]-1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1833]2-[[N,N-Bis(2-hydroxyethyl)carbamoyl]methyl]-1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1834]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1835]1-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1836]2-[[N,N-Bis(2-methoxyethyl)carbamoyl]methyl]-1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1837]2-[[N,N-Bis(2-methoxyethyl)carbamoyl]methyl]-1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1838]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)-N-methylcarbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1839]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)-N-methylcarbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1840]2-[[N-Benzyl-N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1841]2-[[N-Benzyl-N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1842]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(morpholin-4-yl)carbonyl]ethyl]piperazine

[1843]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(dimethylaminocarbonyl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1844]4-[(6-CChlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(pyrrolidin-1-yl)carbonyl]ethyl]piperazine

[1845]2-[2-(Aminosulfonyl)ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1846]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(morpholin-4-yl)sulfonyl]ethyl]piperazine

[1847]2-[2-[(t-Butoxycarbonylamino)sulfonyl]ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1848]2-[2-[(n-Butoxycarbonylamino)sulfonyl]ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1849]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(ethoxycarbonylamino)sulfonyl]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1850]2-[2-(Acetylamino)sulfonyl]ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1851]2-(Aminosulfonylmethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1852]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)sulfonylmethyl]piperazine

[1853]4-[(6-Chlorobenzo[b]thien-2=yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(pyrrolidin-1-yl)sulfonylmethyl]piperazine

[1854]2-[(t-Butoxycarbonylamino)sulfonylmethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1855]2-[(n-Butoxycarbonylamino)sulfonylmethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1856]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(ethoxycarbonylamino)sulfonylmethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1857]2-[(Acetylamino)sulfonylmethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1858]2-[3-[(4H-5-Acetoxy-4-oxo)pyran-2-yl]propyl-3-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1859]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[3-[(4H-5-hydroxy-4-oxo)pyran-2-yl]propyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1860]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[3-[(4H-5-methoxy-4-oxo)pyran-2-ylpropyl-3-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1861]N-methyl-N-[[4-[(6-chlorobenzo[b]thien-2-yl)sulfnyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylpiperazin-2-yl]acetyl]methanesulfonamide

[1862]N-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl-3-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]benzenesulfonamide

[1863]N-[2-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-yl]ethyl]trifluoromethanesulfonamide

[1864]N-methyl-N-[2-[4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]trifluoromethanesulfonamide

[1865]N-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]-N′-methanesulfonylhydrazine

[1866]4-[(6-Chlorobenzo[blthien-2-yl)sulfonyl]-2-[(2-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1867]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-ylethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1868]4-[(6-Chlorobenzo[b]thien-2-yl]sulfonyl-3-2-[2-(2-oxo-3H1,2,3,5-oxathiadiazol-4-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1869]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(2-oxo-3H1,2,3,5-oxathiadiazol-4-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1870]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1871]4-[(6-Chlorobenzo[blthien-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1872]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1873]4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1874]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo-1,3-oxazolan-3-yl)ethyl]piperazine

[1875]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo-1,3-oxazolan-3-yl)ethyl]piperazine

[1876]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo1,3-oxazolan-3-yl)ethyl]piperazine

[1877]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxopyridin-1-yl)ethyl]piperazine

[1878]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxopyridin-1-yl)ethyl]piperazine

[1879]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-[(coumarin-7-yl)oxy]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1880]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-[(coumarin-7-yl)oxy]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1881]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-[(cyclopropylcarbonyl)amino]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1882]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-[(cyclopropylcarbonyl)amino]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1883]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[(cyclopropylcarbonyl)amino]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1884]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(cyclopropylcarbonyl)amino]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1885]2-[2-(Aminosulfonyl)ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1886]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(morpholin-4-yl)sulfonyli ethyl] piperazine

[1887]2-[2-[(t-Butoxycarbonylamino)sulfonyl]ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1888]2-[2-[(n-Butoxycarbonylamino)sulfonyl]ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1889]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(ethoxycarbonylamino)sulfonyl]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1890]2-[2-(Acetylamino)sulfonyl]ethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1891]2-[2-(Aminosulfonyl)ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1892]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(morpholin-4-yl)sulfonyl]ethyl]piperazine

[1893]2-[2-[(t-Butoxycarbonylamino)sulfonyl]ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1894]2-[2-[(n-Butoxycarbonylamino)sulfonyl]ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1895]2-[2-(Ethoxycarbonylamino)sulfonyl]ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1896]2-[2-(Acetylamino)sulfonyl]ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1897]2-(Aminosulfonylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1898]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)sulfonylmethyl]piperazine

[1899] 4-[(5-Chloroindol-2-yl)sylfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(pyrrolidin-1-yl)sulfonylmethyl]piperazine

[1900]2-[(t-Butoxycarbonylamino)sulfonylmethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1901]2-[(n-Butoxycarbonylamino)sulfonylmethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1902]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(ethoxycarbonylamino)sulfonylmethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1903]2-[(Acetylamino)sulfonylmethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1904]2-(Aminosulfonylmethyl)-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1905]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)sulfonylmethyl]piperazine

[1906]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(pyrrolidin-1-yl)sulfonylmethyl]piperazine

[1907]2-[(t-Butoxycarbonylamino)sylfonylmethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1908]2-[(n-Butoxycarbonylamino)sulfonylmethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1909]2-[(Ethoxycarbonylamino)sulfonylmethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1910]2-[(Acetylamino)sulfonylmethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1911]2-[3-[(4H-5-Acetoxy-4-oxo)pyran-2-yl]propyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1912]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[3-[(4H-5-hydroxy-4-oxo)pyran-2-yl]propyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1913]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[3-[(4H-5-methoxy-4-oxo)pyran-2-yl]propyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1914]N-[[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]-N-methylmethanesulfonamide

[1915]N-[[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]benzenesulfonamide

[1916]N-[2-[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]trifluoromethanesulfonamide

[1917]N-[2-[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]-N-methyltrifluoromethanesulfonamide

[1918] N-[[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]-N′-methanesulfonylhydrazine

[1919]2-[3-[(4H-5-Acetoxy-4-oxo)pyran-2-yl]propyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1920]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[3-[(4H-5-hydroxy-4-oxo)pyran-2-yl]propyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1921]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[3-[(4H-5-methoxy-4-oxo)pyran-2-yl]propyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1922]N-methyl-N-[[4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]methanesulfonamide

[1923]N-[[4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]benzenesulfonamide

[1924]N-[2-[4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]trifluoromethanesulfonamide

[1925]N-[2-[4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]-N-methyltrifluoromethanesulfonamide

[1926]N-[[4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]-N′-methanesulfonylhydrazine

[1927]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1928]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1929]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1930]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1931]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl)ethyl]piperazine

[1932]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl)ethyl]piperazine

[1933]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo3H-1,2,3,5-oxathiadiazol-4-yl)ethyl]piperazine

[1934]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(2-oxo3H-1,2,3,5-oxathiadiazol-4-yl)ethyl]piperazine

[1935]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1936]2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1937]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1938]2-[2-(2,5-Dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1939]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1940]2-[2-(2,5-Dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-4-[(5-ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1941]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1942]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[2-(2,5-dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1943]1-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1944]2-[[N,N-Bis(2-hydroxyethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1945]2-[[N,N-Bis(2-hydroxyethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1946]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1947]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)carbamoyl]methyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1948]2-[[N,N-Bis(2-methoxyethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1949]2-[[N,N-Bis(2-methoxyethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1950]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)N-methylcarbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1951]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(2-hydroxyethyl)N-methylcarbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1952]2-[[N-Benzyl-N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1953]2-[[N-benzyl-N-(2-hydroxyethyl)carbamoyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1954]4-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1955]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-cyanomethyl-N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1956]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-cyanomethyl-N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1957]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(morpholin-4-yl)carbonyl]ethyl]piperazine

[1958]4-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(dimethylaminocarbonyl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1959]4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(pyridin-1-yl)carbonyl]ethyl]piperazine

[1960]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(morpholin-4-yl)carbonyl]ethyl]piperazine

[1961]4-[(5-Ethynylindol-2-yl)sulfonyl]-2-[2-(dimethylaminocarbonyl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1962]4-[(5-Ethynylindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-[(pyridin-1-yl)carbonyl]ethyl]piperazine

[1963]2-(3-Butynyl)-4-[(5-chloroindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1964]2-(3-Butynyl)-4-[(5-chloroindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[1965]4-[(6-Chloro-3-hydroxybenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1966]4-[(6-Chloro-3-hydroxybenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1967]4-[(6-Chloro-3-hydroxybenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1968]4-[(6-Chloro-3-hydroxybenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1969]4-[(6-Chloro-3-hydroxybenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1970]4-[(6-Chloro-3-hydroxybenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1971]4-[(3-Acetyl-6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1972]4-[(3-Acetyl-6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1973]4-[(3-Acetyl-6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1974]4-[(3-Acetyl-6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1975]4-[(3-Acetyl-6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1976]4-[(3-Acetyl-6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1977]4-[(6-Chloro-3-(hydroxymethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1978]4-[(6-Chloro-3-(hydroxymethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1979]4-[(6-Chloro-3-(hydroxymethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1980]4-[(6-Chloro-3-(hydroxymethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1981]4-[(6-Chloro-3-(hydroxymethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1982]4-[(6-Chloro-3-(hydroxymethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1983]4-[(6-Chloro-3-(N,N-dimethylaminomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1984]4-[(6-Chloro-3-(N,N-dimethylaminomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1985]4-[(6-Chloro-3-(N,N-dimethylaminomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1986]4-[(6-Chloro-3-(N,N-dimethylaminomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1987]4-[(6-Chloro-3-(N,N-dimethylaminomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1988]4-[(6-Chloro-3-(N,N-dimethylaminomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1989]4-[(6-Chloro-3-(cyanomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1990]4-[(6-Chloro-3-(cyanomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1991]4-[(6-Chloro-3-(cyanomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1992]4-[(6-Chloro-3-(cyanomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1993]4-[(6-Chloro-3-(cyanomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1994]4-[(6-Chloro-3-(cyanomethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[1995]4-[(6-Chloro-3-(carbamoylmethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1996]4-[(6-Chloro-3-(carbamoylmethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[1997]4-[(6-Chloro-3-(carbamoylmethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1998]4-[(6-Chloro-3-(carbamoylmethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[1999]4-[(6-Chloro-3-(carbamoylmethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2000]4-[(6-Chloro-3-(carbamoylmethyl)benzo[b]thien-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2001]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2002]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2003]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-hydroxymethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2004]1-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-4-[(6-hydroxymethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[2005]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N,N-dimethylcarbamoylmethyl)piperazine

[2006]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N,N-dimethylcarbamoylmethyl)piperazine

[2007]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(2-cyanoethyl)piperazine

[2008]4-[(5-Chloro-3-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(2-cyanoethyl)piperazine

[2009]4-[(3-Acetyl-5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2010]4-[(3-Acetyl-5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2011]4-[(3-Acetyl-5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N,N-dimethylcarbamoylmethyl)piperazine

[2012]4-[(3-Acetyl-5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(N,N-dimethylcarbamoylmethyl)piperazine

[2013]4-[(3-Acetyl-5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2(2-cyanoethyl)piperazine

[2014]4-[(3-Acetyl-5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2(2-cyanoethyl)piperazine

[2015]4-[(5-Chloro-3-(hydroxymethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2016]4-[(5-Chloro-3-(hydroxymethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2017]4-[(5-Chloro-3-(hydroxymethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2018]4-[(5-Chloro-3-(hydroxymethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2019]4-[(5-Chloro-3-(hydroxymethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2020]4-[(5-Chloro-3-(hydroxymethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2021]4-[(5-Chloro-3-(N,N-dimethylaminomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2022]4-[(5-Chloro-3-(N,N-dimethylaminomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2023]4-[(5-Chloro-3-(N,N-dimethylaminomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2024]4-[(5-Chloro-3-(N,N-dimethylaminomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2025]4-[(5-Chloro-3-(N,N-dimethylaminomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2026]4-[(5-Chloro-3-(N,N-dimethylaminomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2027]4-[(5-Chloro-3-(cyanomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2028]4-[(5-Chloro-3-(cyanomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2029]4-[(5-Chloro-3-(cyanomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2030]4-[(5-Chloro-3-(cyanomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2031]4-[(5-Chloro-3-(cyanomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2032]4-[(5-Chloro-3-(cyanomethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2033]4-[(5-Chloro-3-(carbamoylmethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2034]4-[(5-Chloro-3-(carbamoylmethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-ylcarbonyl)methyl]piperazine

[2035]4-[(5-Chloro-3-(carbamoylmethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2036]4-[(5-Chloro-3-(carbamoylmethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N,N-dimethylcarbamoylmethyl)piperazine

[2037]4-[(5-Chloro-3-(carbamoylmethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2038]4-[(5-Chloro-3-(carbamoylmethyl)indol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(2-cyanoethyl)piperazine

[2039]4-[(5-Chloro-1-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2040]4-[(5-Chloro-1-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2041]4-[(5-Chloro-1-methoxyindol-2-yl)sulfonyl]-1-[(6-methyl4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2[(morpholin-4-yl)carbonylmethyl]piperazine

[2042]4-[(5-Chloro-1-methoxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2043]4-[4-[(6-Chloro-1-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2044]4-[4-[(6-Chloro-1-hydroxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2045]4-[4-[(6-chloro-1-methoxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2046]4-[4-[(6-Chloro-1-methoxyindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[(morpholin-4-yl)carbonylmethyl]piperazine

[2047] In the present invention, in addition to the aboveexemplifiedcompounds, salts thereof and solvates thereof can be mentioned aspreferred examples.

[2048] The process for the preparation of the sulfonyl derivative of thepresent invention will next be described.

[2049] The sulfonyl derivative or salt thereof, or solvate thereofaccording to the present invention can be prepared by using general,conventionally-known chemical processes in combination. Typicalsynthesis processes will be described subsequently.

[2050] Upon synthesis of the sulfonyl derivative of the presentinvention, when it is necessary to protect a substituent such asnitrogen atom, hydroxyl group or carboxyl group, it may be protectedwith an ordinary, conventionally-known protecting group which can beremoved as needed. Such a protecting group can be removed at need by thesynthesis process ordinarily employed in the organic chemistry whichwill be described below.

[2051] The starting materials necessary for the synthesis can beobtained by the synthesis process ordinarily employed in the organicchemistry and such a process will be described in Referential Examples.The starting materials for the sulfonyl derivative of the presentinvention can also be synthesized by the application of the processdescribed in Referential Examples.

[2052] A description will next be made of a protecting group for thesubstituent such as nitrogen atom, hydroxyl group or carboxyl group anddeprotection process thereof.

[2053] As a protecting group for the nitrogen atom in an amino oralkylamino group, ordinary acyl-type protecting groups are suited.Examples include alkanoyl groups such as acetyl, alkoxycarbonyl groupssuch as methoxycarbonyl, ethoxycarbonyl and tertiary butoxy carbonyl,arylmethoxycarbonyl groups such as benzyloxycarbonyl,paramethoxybenzyloxycarbonyl and para-(ortho)nitrobenzyloxycarbonylgroups, arylmethyl groups such as benzyl and triphenylmethyl and aroylgroups such as benzoyl. The removing process of such a protecting groupdiffers with the chemical properties of the protecting group adopted.For example, the acyl-type protecting group such as alkanoyl.,alkoxycarbonyl or aroyl can be removed by hydrolysis using anappropriate base such as alkali metal hydroxide, for example, lithiumhydroxide, sodium hydroxide or potassium hydroxide.

[2054] The substituted methoxycarbonyl type protecting group such astertiary butoxycarbonyl or paramethoxybenzyloxycarbonyl can be removedby using an appropriate acid, for example, acetic acid, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroaceticacid or trifluoromethanesulfonic acid or combination thereof. Thearylmethoxycarbonyl group such as benzyloxycarbonyl,paramethoxybenzyloxycarbonyl or para-(ortho)nitrobenzyloxycarbonyl, orthe arylmethyl group such as benzyl can be removed by hydrogenolysis inthe presence of a palladium-carbon catalyst. The benzyl group can alsobe removed by Birch reduction, in liquid ammonia, in the presence of ametal sodium, whereby conversion into a nitrogenhydrogen bond can beeffected. The triphenylmethyl group can be removed by using anappropriate acid such as formic acid, acetic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acidor trifluoromethanesulfonic acid or combination thereof it can also beremoved by Birch reduction, in liquid ammonia, in the presence of ametal sodium or by hydrogenolysis in the presence of a palladium-carboncatalyst.

[2055] In addition to the above-described amino-protecting group, aphthaloyl type protecting group can be adopted for a primary amino groupand it can be removed using hydrazine, dimethylaminopropylamine or thelike. The amino group can also be protected with the nitrogen atom ofindole, a phenylsulfonyl group, a toluenesulfonyl group, an acetylgroup, a trifluoroacetyl group or the like and deprotection can becarried out by hydrolysis using a proper base such as sodium hydroxide,lithium hydroxide or potassium hydroxide.

[2056] As the protecting group suited for a hydroxyl group, there areacyl type and ether type ones. Examples of the acyl type protectinggroup include alkanoyl groups such as acetyl and aroyl groups such asbenzoyl, while those of the ether type protecting group includearylmethyl groups such as benzyl, silyl ether groups such as tertiarybutyl dimethylsilyl, methoxymethyl and tetrahydropyranyl. The removal ofsuch a protecting group differs with the chemical properties of theprotecting group adopted. For example, the acyl group such as alkanoylor aroyl can be removed by the hydrolysis using an appropriate base suchas an alkali metal hydroxide, for example, lithium hydroxide, sodiumhydroxide or potassium hydroxide. The arylmethyl type protecting groupcan be removed by the hydrogenolysis using a palladium-carbon catalyst.The silyl group such as tertiary butyl dimethylsilyl can be removedusing a salt of hydrofluoride such as tetrabutyl ammonium fluoride. Themethoxymethyl or tetrahydropyranyl group can be removed using aceticacid, hydrochloric acid or the like. The hydroxyl group substituted foran aryl group can be protected with a methyl group and deprotection canbe carried out using a Lewis acid such as aluminum chloride, borontrifluoride or phosphorus tribromide, trimethylsilyl iodide or hydrogenbromide.

[2057] A carboxyl group can be protected by the esterification of it. Amethyl or ethyl ester can be deprotected by the hydrolysis using anappropriate base such as alkali metal hydroxide, e.g., lithiumhydroxide, sodium hydroxide or potassium hydroxide, while from atertiary butyl ester, the tertiary butyl group can be removed bytreating with trifluoroacetic acid or hydrochloric acid. From anarylmethyl type ester such as benzyl, the arylmethyl group can beremoved by the hydrogenolysis in the presence of a palladium-carboncatalyst.

[2058] As the protecting group for acetylene, an alkylsilyl group suchas trimethylsilyl, tertiary-butyldimethylsilyl ortertiary-butyldiphenylsilyl can be employed and deprotection can becarried out using a proper base, for example, an alkali metal hydroxidesuch as sodium hydroxide, lithium hydroxide or potassium hydroxide or asalt of hydrofluoride such as tetrabutylammonium fluoride or pyridinehydrofluoride.

[2059] [Preparation Process-1]

[2060] A process for preparing a sulfonyl derivative represented by thefollowing formula (I):

Q¹-Q²-T¹-Q³-SO₂-Q^(A)  (I)

[2061] [wherein Q¹, Q², Q³, Q^(A) and T¹ have the same meanings asdescribed above], which comprises sulfonylating the nitrogen atom ofQ^(3a) of the compound represented by the following formula (Ia):

Q¹-Q²=T¹=Q^(3a)  (Ia)

[2062] [wherein Q¹, Q² and T¹ have the same meanings as described aboveand Q^(3a) represents any one of the groups represented by the followingformulas:

[2063] (in which R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², a, b, c d,e, f, g, h and i have the same meanings as described above)] with asulfonic acid halide represented by the following formula (IIa):

Halo-SO₂-Q^(A)  (IIa)

[2064] [wherein Q^(A) has the same meaning as described above and Halorepresents a halogen atom such as chlorine, bromine or iodine].

[2065] <Synthesis of the Compound of the Formula (Ia)>

[2066] The compound of the formula (Ia) can be synthesized by a seriesof procedures in accordance with the known technique.

[2067] For example, a compound of the following formula (Ib):

Q¹-Q²-T¹-Q^(3b)  (Ib)

[2068] [wherein Q¹, Q² and T¹ have the same meanings as decscribed aboveand Q^(3b) represents any one of the following groups:

[2069] (wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², a, b, c, d,e, f, g, h and i have the same meanings as described above and R²¹represents an ordinary nitrogen protecting group such as tertiarybutoxycarbonyl, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl,paranitrobenzyloxycarbonyl or benzyl)] can be synthesized by acylatingthe nitrogen atom of the compound—which can be synthesized in aconventionally known manner or by application thereof and is representedby the following formula (IIIa):

Q^(3b)-H  (IIIa)

[2070] (wherein Q^(3b) has the same meaning as described above)—to whichthe hydrogen atom of Q^(3b) has been bonded, with a carboxylic acid inan activated form represented by any one of the following formulas (Iva)to (Ivd):

Q¹-Q^(2b)-COOH  (IVa)

Q¹-N-(R²⁰)—(CH₂)_(m1)—COOH  (IVb)

Q¹-O—(CH₂)_(m1)—COOH  (IVc)

Q¹-S—(CH₂)_(m1)—COOH  (IVd)

[2071] [wherein Q¹ has the same meaning as described above, R²⁰represents an ordinary nitrogen protecting group such as linear orbranched alkylkylene, tertiary butoxycarbonyl, benzyloxycarbonyl,paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl or benzyl,Q^(2b) represents a single bond, a linear or branched C₁₋₆ alkylene, alinear or branched C₂₋₆ alkenylene, a linear or branched C₂₋₆ alkynyleneor a group of the following formula:

[2072] (which has the same meaning as described above) and m1 stands foran integer of 1 to 6].

[2073] When the nitrogen atom of Q^(3b) of the compound represented bythe formula (IIIa) forms an amide bond, the compound of the formula (Ib)can be synthesized by alkylating the nitrogen atom of Q^(3b) of thecompound represented by the formula (IIIa) with any one of the compoundsrepresented by the following formulas (Va) to (Vd):

Q¹-Q^(2b)-CHL¹R¹³  (Va)

Q¹-N-(R²⁰)—(CH₂)_(m1)—CHL¹R¹³  (Vb)

Q¹-O—(CH₂)_(m1)—CHL¹R¹³  (Vc)

Q¹-S—(CH₂)_(m1)—CHL¹R¹³  (Vd)

[2074] [wherein Q¹, Q^(2b), R¹³, R²⁰ and m1 have the same meanings asdescribed above, and L¹ represents an eliminating group frequently usedin the organic chemistry, such as chlorine, bromine, iodine,methylsulfonyloxy or paratoluenesulfonyloxy].

[2075] When the nitrogen atom of Q^(3b) of the compound represented bythe formula (IIIa) exists as a primary or secondary amine, the compoundof the formula (Ib) can be prepared by reductive alkylation, that is, byforming the corresponding imine with a carbonyl compound represented byany one of the following formulas (VIa) to (VId):

Q¹-Q^(2b)-C(═O)R¹³  (VIa)

Q¹-N-(R²⁰)—(CH₂)_(m1)—C(═O)R¹³  (VIb)

Q¹-O— (CH₂)_(m1)—C(═O)R¹³  (VIc)

Q¹-S—(CH₂)_(m1)—C(═O)R¹³  (VId)

[2076] [wherein Q¹, Q^(2b), R¹³, R²⁰ and m1 have the same meanings asdescribed above], followed by reduction; by reacting the compound of theformula (IIIa) with a reagent such as phosgene, triphosgene or1,1′-carbonyldiimidazole and a compound containing a primary aminerepresented by any one of the following formulas (VIIa) to (VIId) orformula (VIIe):

Q¹-Q^(2b)-NH₂  (VIIa)

Q¹-N-(R²⁰)—(CH₂)_(m2)—NH₂  (VIIb)

Q¹-O—(CH₂)_(m2)—NH₂  (VIIc)

Q¹-S—(CH₂)_(m2)—NH₂  (VIId)

[2077] wherein Q¹, Q^(2b) and R²⁰ have the same meanings as describedabove and m2 stands for an integer of 2 to 6 and a group of thefollowing formula:

[2078] represents a 5- or 6-membered heterocyclic group which may have asubstituent)], thereby forming the corresponding urea derivative; or byreacting the amine of the formula (IIIa) with an isocyanate derivativeor an isocyanate prepared from a carboxylic acid represented by any oneof the formulas (IVa) to (IVd).

[2079] When in the structure of Q¹ of the compound represented by theformula (Ib), a halogen- or trifluoromethanesulfonyloxy-substituted arylgroup or a halogen- or trifluoromethanesulfonyloxy-substituted alkenylgroup is contained, coupling reaction can be effected with aboricacid-substituted aryl compound in the presence of a transitionmetal catalyst.

[2080] When in the structure of Q¹ of the compound represented by theformula (Ib), an alkenyl group or boric-acidsubstituted alkenyl group iscontained, it can be subjected to coupling reaction with a halogen- ortrifluoromethanesulfonyloxy-substituted aryl group in the presence of atransition metal catalyst.

[2081] When in the structure of Q¹ of the compound represented by theformula (Ib), a boric-acid-substituted aryl group is contained, it canbe subjected to coupling reaction with a halogen- ortrifluoromethanesulfonyloxysubstituted aryl compound or a halogen- ortrifluoromethanesulfonyloxy-substituted alkenyl compound. When in thestructure of Q¹ of the compound represented by the formula (Ib), ahalogen- or trifluoromethanesulfonyloxysubstituted aryl group iscontained, it can be subjected to coupling reaction with an alkenylcompound in the presence of a transition metal catalyst, whereby thecompound of the formula (Ib) can be obtained. If the nitrogen atom ofQ^(3b) of the compound (Ib) so obtained has been protected, the compoundof the formula (Ia) can be obtained by deprotection as needed.

[2082] Examples of the carboxylic acids of the-following formulas (IVa)to (IVd) in an activated form include acid mixed acid anhydridesavailable by reacting any one of the carboxylic acids of the formulas(IVa) to (IVd) with a chloroformate ester such as isobutylchloroformate; acid halides such as acyl chloride prepared using an acidhalide such thionyl chloride; active esters obtained by reacting with aphenol such as paranitrophenol or pentafluorophenyltrifluoroacetate;active esters obtained by reacting with N-hydroxybenztriazole orN-hydroxysuccinimide; reaction products with1-benztriazolyloxy-(pyrrolidino)-phosphonium hexafluorophosphite,N,N′-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride which isusually employed for the peptide synthesis of amino acid, reactionproducts with diethyl cyanophosphonate (salting-in method) and reactionproducts with triphenylphosphine and 2,2′-dipyridylsulfide (Mukaiyama'smethod).

[2083] The resulting carboxylic acid in an activated form is thenreacted with the compound of the formula (IIIa) or salt thereofgenerally in the presence of an appropriate base in an inert solvent at−78° C. to 150° C., whereby the compound of the formula (Ib) can beobtained.

[2084] Specific examples of the base include carbonates, alkoxides,hydroxides and hydrides of an alkali metal or alkaline earth metal, suchas sodium carbonate, potassium carbonate, sodium ethoxide, potassiumbotoxide, sodium hydroxide, potassium hydroxide, sodium hydride andpotassium hydride; organometallic base compounds typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bissilylamine compounds such aslithium bis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2085] Examples of the inert solvent include alkyl halide solvents suchas dichloromethane, chloroform and carbon tetrachloride; ether solventssuch as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromaticsolvents such as benzene and toluene; and amide solvents such asN,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one. In addition to them, sulfoxide solvents suchas dimethylsulfoxide and sulfolane and ketone solvents such as acetoneand methyl ethyl ketone can be used if they are suited.

[2086] When the nitrogen atom of Q^(3b) of the compound represented bythe formula (IIIa) forms an amide bond, the alkylation of the nitrogenatom is carried out by reacting the compound (IIIa) with the compoundrepresented by any one of the formulas (Va) to (Vd) in the presence ofan appropriate base in an inert solvent at −78 to 150° C., whereby thecompound of the formula (Ib) can be obtained. Specific exampes of thebase include alkoxides and hydrides of an alkali metal or alkaline earthmetal such as sodium ethoxide, potassium butoxide, sodium hydride andpotassium hydride; organometallic base compounds typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bissilylamine compounds such aslithium bis(trimethylsilyl)amide; and organic bases such asdiazabicyclo[5.4.0]undec-7-ene (DBU).

[2087] Examples of the inert solvent include ether solvents such astetrahydrofuran, 1,2-dimethoxyethane and dioxane and amide solvents suchas N,N-dimethylformamide.

[2088] When the nitrogen atom of Q^(3b) of the compound represented bythe formula (IIIa) exists as a primary or secondary amine, the compoundof the formula (Ib) can be obtained by reacting the compound of theformula (IIIa) with the carbonyl compound of any one of the formulas(VIa) to (VId) to form the corresponding imine, generally in an inertsolvent, optionally in the presence of an organic acid such as aceticacid, a mineral acid such as hydrochloric acid or a Lewis acid such asaluminum chloride at −20 to 150° C.; and then hydrogenating theresulting imine in an inert solvent in the presence of a boron hydridereducing agent such as sodium borohydride, sodium cyanoborohydride orsodium triacetoxyborohydride or a catalytic hyddrogenation catalyst suchas palladium-carbon catalyst at 10 to 110° C.

[2089] Preferred examples of the inert solvent include carbon halidessuch as dichloromethane, chloroform and carbon tetrachloride, ethersolvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane,benzene solvents such as toluene and amide solvents such asN,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one.

[2090] When the nitrogen atom of Q^(3b) of the compound represented bythe formula (IIIA) exists as a primary or secondary amine, the reactionproduct of the compound of any one of the formulas (VIIa) to (VIId)containing a primary amine or the compound of the formula (VIIe)containing a secondary amine with a reagent such as phosgene,triphosgene or 1,1′-carbonyldiimidazole can be acted on the compound ofthe formula (IIIa) to introduce it to the corresponding urea derivative.The derivative can be synthesized by reacting the primary amine compoundof any one of the formulas (VIIa) to (VIId) or the secondary aminecompound of the formula (VIIe), a reagent such as phosgene, triphosgeneor 1,1′-carbonyldiimidazole and the compound of the formula (IIIa)successively in this order, if necessary in the presence of a base, inan inert solvent.

[2091] Examples of the inert solvent include halogen solvents such asdichloromethane, chloroform and carbon tetrachloride; ether solventssuch as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; benzenesolvents such as toluene; and amide solvents such asN,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one. Among them, dichloromethane, tetrahydrofuranand toluene are preferred.

[2092] Examples of the base include carbonates and hydroxides of analkali metal or alkaline earth metal, such as sodium carbonate,potassium carbonate, sodium hydroxide and potassium hydroxide; andorganic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU). Thereaction is effected within a temperature range of from −70° C. to 110°C.

[2093] When the nitrogen atom of Q^(3b) of the compound represented bythe formula (IIIa) exists as a primary or secondary amine, the compoundof the formula (Ib) can also be obtained by reacting the compound of theformula (IIIa) with an isocyanate derivative in an inert solvent at −20to 100° C.

[2094] The isocyanate derivative can be synthesized by converting thecarboxylic acid of the formula (IVa) into the corresponding acid halideby using an acid halide such as thionyl chloride or oxalyl chloride inan inert solvent such as tetrahydrofuran, chloroform or toluene at −20to 110° C., reacting the resulting acid halide with sodium azide in aninert solvent such as tetrahydrofuran, chloroform or toluene at atemperature range of from 0 to 80° C., and then heating the reactionmixture at 20 to 100° C.; by reacting the carboxylic acid of the formula(IVa) with a chloroformate such as isobutyl chloroformate in an inertsolvent such as tetrahydrofuran, chloroform or toluene at −20 to 110° C.to obtain the corresponding mixed acid anhydride, reacting the mixedacid anhydride with sodium azide within a temperature range of from 0 to80° C. and then heating the reaction mixture at 20 to 100° C.; or byintroducing the carboxylic acid of the formula (IVa) into thecorresponding hydrazide through an ester in an inert solvent such astetrahydrofuran, chloroform or toluene at −20 to 110° C., reacting thehydrazide with nitric acid or alkyl ester thereof to convert it into thecorresponding acyl azide and then heating the resulting acyl azide in asolvent such as chloroform, dichloroethane, toluene, xylene orN,N-dimethylformamide at 20 to 150° C.

[2095] The compound of the formula (Ib) can also be prepared by reactingthe carboxylic acid of the formula (IVa) with diphenylphosphoryl azidein the presence of a base such as triethylamine, in an inert solventsuch as chloroform, tetrahydrofuran, toluene or N,N-dimethylformamide ata temperature range of 10 to 140° C. and then reacting the reactionmixture with the amine of the formula (IIIa).

[2096] When in the structure of Q¹ of the compound represented by theformula (Ib), a halogen- or trifluoromethanesulfonyloxy-substituted arylgroup or a halogen- or trifluoromethanesulfonyoxy-substituted alkenylgroup is contained, the compound can be subjected to coupling reactionwith a boric-acid-substituted aryl derivative by using a transitionmetal catalyst such as tetrakis(triphenylphosphine)palladium (O), in atwo-phase solvent such as benzene-water or toluene-water, amide solventsuch as N,N-dimethylformamide or ether solvent such as tetrahydrofuranor dimethoxyethane, optionally in the presence of as sodium carbonate,sodium hydroxide, barium hydroxide, potassium phosphate or cesiumcarbonate at a temperature range of 20 to 150° C. for 0.5 to 120 hours.

[2097] When an alkenyl group or boric-acid-substituted alkenyl group iscontained in the structure of Q¹ of the compound represented by theformula (Ib), coupling reaction of the compound with a halogen- ortrifluoromethanesulfonyloxy-substituted aryl group can be effected usinga transition metal catalyst such as palladium acetate, in the presenceof an appropriate base or cesium fluoride, in an amide solvent such asN,N-dimethylformamide, at a temperature range of 20 to 150° C. for 0.5to 120 hours. When a boricacid-substituted aryl group is contained inthe structure of Q¹ of the compound represented by the formula (Ib),coupling reaction of the compound with a halogen- ortrifluoromethanesulfonyloxy-substituted aryl derivative or a halogen- ortrifluoromethanesulfonyloxy-substituted alkenyl derivative can beeffected. When a halogen- or trifluoromethanesulfonyloxy-substitutedaryl group is contained in the structure of Q¹ of the compoundrepresented by the formula (Ib), coupling reaction of the compound withan alkenyl compound can be effected using a transition metal catalyst,whereby the compound of the formula (Ib) can be obtained.

[2098] If the nitrogen atom of Q^(3b) of the resulting compoundrepresented by the formula (Ib) has been protected, the compound of theformula (Ia) can be obtained by deprotection as needed.

[2099] <Synthesis of the Compound Represented by the Formula (IIa)>

[2100] The sulfonic acid halide of the formula (IIa) can be synthesizedin a known matter or by application thereof. The ordinarily employedsynthesis process will be described below.

[2101] Among the sulfonic acid halides represented by the formula (IIa),a sulfonic acid halide represented by the following formula (IIa-1a):

[2102] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹, X² and Halo have the samemeanings as described above] can be synthesized by any one of thevarious processes reported to date (The Chemistry of Sulfonic AcidsEsters and their Derivatives, Edited by S. Patai and Z. Rappoport, 1991,John Wiley & Sons Ltd.), for example, halogenation of a sulfonic acid ofthe following formula (IIa-1b):

[2103] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹ and X² have the samemeanings as described above] or chlorosulfonylation of the unsaturatedbond represented by the following formula (IIaIc):

[2104] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹ and X² have the samemeanings as described above].

[2105] For example, the sulfonic acid halide of the formula (IIa-1a) canbe obtained by reacting the sulfonic acid of the formula (IIa-1b) with athionyl halide in the presence of N,N-dimethylformamide at 0 to 150° C.for 0.5 to 24 hours. At this time, the reaction system may be dilutedwith an inert solvent such as dichloromethane, chloroform, carbontetrachloride, N-methylpyrrolidin-2-one, dimethylsulfoxide or sulfolane.

[2106] The sulfonic acid halide of the formula (IIa-1a) can be obtainedby reacting the unsaturated-bond-containing compound of the formula(IIa-1c) with a thionyl halide or chlorosulfonic acid in an inertsolvent such as N,N-dimethylformamide at 0 to 150° C. for 0.5 to 24hours.

[2107] Among the sulfonic acid halides represented by the formula (IIa),a sulfonic acid halide represented by the following formula (IIa-2a):

[2108] [wherein X³, X⁴, X⁵, X⁶, X⁷, X⁸ and Halo have the same meaningsas described above] can be obtained by the processes so far reported(Japanese Patent Application Laid-Open No. Sho 60-204760, JapanesePatent Application Laid-Open No. Sho 62-116575, Japanese PatentApplication Laid-Open No. Hei 4-128266) or by application thereof, forexample, by reacting the fused heterocycle represented by the followingformula (IIa-2b):

[2109] [wherein X³, X⁴, X⁵, X⁶, X⁷ and X⁸ have the same meanings asdescribed above] with a base and then sulfur dioxide and then reactingthe reaction mixture with a halogenating agent.

[2110] The compound of the formula (IIa-2a) is obtained, for example, byreacting the fused heterocycle of the formula (IIa-2b) with anappropriate base in an ether-type inert solvent at −78° C. to 0° C.,reacting the reaction mixture with sulfur dioxide at −78° C. to 0° C.,and then reacting with a halogenating agent in an alkyl halide typeinert solvent at −50° C. to 50° C. Specific examples of the base includealkoxides and hydrides of an alkali metal or alkaline earth metal suchas sodium ethoxide, potassium botoxide, sodium hydride and potassiumhydride; organometallic base compounds typified by alkyl lithium such asn-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bisssilylamine compounds suchas lithium bis(trimethylsilyl)amide. Examples of the ethertype inertsolvent include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane anddioxane. Preferred examples of the halogenating agent include chlorine,bromine, phosphorus pentachloride, thionyl chloride, N-chlorosuccinimideand N-bromosuccinimide, while those of the alkyl halide type inertsolvent include dichloromethane, chloroform and tetrachloroethane.

[2111] Among the compounds represented by the formula (IIa-2a), thecorresponding sulfonyl chloride of the compound represented by thefollowing formula (IIa-2c):

[2112] [wherein R¹⁰¹, X⁵, X⁶ X⁷, X⁸ and Halo have the same meanings asdescribed above] can be obtained by reacting the compound of thefollowing formula (IIa-2d):

[2113] [wherein R¹⁰¹, X⁵, X⁶, X⁷ and X⁸ have the same meanings asdescribed above] with halogen such as a chlorine gas at 0 to 30° C. for10 minutes to 6 hours in water or a mixed solvent of water with anorganic carboxylic acid such as acetic acid.

[2114] The reaction between the compound of the formula (IIa-2d) andhalogen is carried out at 0 to 20° C. usually in water or a 10 to 90%aqueous solution of acetic acid if necessary in the presence of a Lewisacid such as ferric chloride as a catalyst.

[2115] <Reaction of a Compound of the Formula (Ia) with a Compound ofthe Formula (IIa)>

[2116] The compound of the formula (I) can be obtained generally byreacting the compound of the formula (Ia), which has been synthesized bythe above-described process or the like, with the sulfonic acid halideof the formula (IIa) which has been synthesized by the above-describedprocess or the like, in the presence of an appropriate base, in an inertsolvent at −78 to 150° C.

[2117] The resulting compound of the formula (I) can be subjected todeprotection or chemical conversion of a substituent as needed.

[2118] Specific examples of the base include carbonates, alkoxides,hydroxides and hydrides of an alkali metal or alkaline earth metal, suchas sodium carbonate, potassium carbonate, sodium ethoxide, potassiumbotoxide, sodium hydroxide, potassium hydroxide, sodium hydride andpotassium hydride; organometallic base compounds typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bissilylamine compounds such aslithium bis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2119] Examples of the inert solvent include dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulfoxide and sulfolane and mixedsolvents thereof.

[2120] [Preparation Process-1-(1)]

[2121] When the nitrogen atom of Q^(3a) of the compound represented bythe formula (Ia), which is to be sulfonylated, exists as a primary orsecondary amine, preferred examples of the base include carbonates andhydroxides of an alkali metal or an alkaline earth metal such as sodiumcarbonate, potassium carbonate, sodium hydroxide and potassium hydroxideand organic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU) andusable examples of the solvent include, in addition to inert solvents,water, alcohol solvents such as ethanol and butanol and ester solventssuch as ethyl acetate.

[2122] [Preparation Process-1-(2)]

[2123] When the nitrogen atom of Q^(3a) of the compound represented bythe formula (Ia), which is to be sulfonylated, forms an amide group,preferred examples of the base include alkoxides and hydrides of analkali metal or an alkaline earth metal such as sodium ethoxide,potassium botoxide, sodium hydride and potassium hydride; organometallicbase compounds typified by alkyl lithium such as nbutyl lithium anddialkylaminolithium such as lithium diisopropylamide; organometallicbase of bissilylamine compounds such as lithiumbis(trimethylsilyl)amide; and organic bases such asdiazabicyclo[5.4.0]undec-7-ene (DBU). Examples of the inert solventinclude tetrahydrofuran, 1,2-dimethoxyethane, dioxane andN,N-dimethylformamide.

[2124] [Preparation Process-2]

[2125] A process for preparing the sulfonyl derivative (I) by acylatingthe nitrogen atom of Q^(3a) of the compound represented by the formula(VIIIa):

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2126] [wherein Q^(3a) and Q^(A) have the same meanings as describedabove] with any one of the carboxylic acids represented by the formulas(IVa) to (IVd):

Q¹-Q^(2b)-COOH  (IVa)

Q¹-N-(R²⁰)—(CH₂)_(m1)—COOH  (IVb)

Q¹-O—(CH₂)_(m1)—COOH  (IVc)

Q¹-S—(CH₂)_(m1)—COOH  (IVd)

[2127] [wherein Q¹, Q², Q^(2b), R²⁰ and m1 have the same meanings asdescribed above] or the activated form thereof which are available bythe process reported to far or the chemically usual process.

[2128] The compound represented by the formula (VIIIa) can besynthesized in various processes. Some of them will next be described.

[2129] <Synthesizing Process of a Compound Represented by the Formula(VIIIa)>

[2130] <Synthesizing Process of a Compound Represented by the Formula(VIIIa-1a)>

[2131] Among the compounds represented by the formula (VIIIa), thecompound of the formula (VIIIa-1a):

[2132] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹, X² and Q^(3a) have the samemeanings as described above] can be synthesized as described below.

[2133] The compound of the following formula (VIIIa-1b):

[2134] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹, X² and Q^(3b) have the samemeanings as described above] can be obtained by sulfonylating thenitrogen atom of the primary amine, secondary amine or amide of thecompound of the formula (IIIa):

Q^(3b)-H  (IIIa)

[2135] [wherein Q^(3b) has the same meaning as described above] with acompound represented by the following formula (IIa-1a):

[2136] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹, X² and Halo have the samemeanings as described above] in the presence of an appropriate base inan inert solvent at −78 to 150° C.

[2137] Specific examples of the base include carbonates, alkoxides,hydroxides and hydrides of an alkali metal or alkaline earth metal, suchas sodium carbonate, potassium carbonate, sodium ethoxide, potassiumbotoxide, sodium hydroxide, potassium hydroxide, sodium hydride andpotassium hydride; organometallic base compounds typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bissilylamine compounds such aslithium bis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2138] Examples of the inert solvent include dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and acetone.

[2139] If the nitrogen atom of Q^(3b) of the resulting compoundrepresented by the formula (VIIIa-1b) has been protected, the compoundof the formula (VIIIa-1a) can be obtained by deprotection as needed.

[2140] The compound of the formula (VIIIa-1a) can be obtained byremoving, in an appropriate manner, the protecting group of the nitrogenatom from the compound represented by the following formula (VIIIa-1c):

[2141] [wherein R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, X¹ and X² have the samemeanings as described above, R²² represents

[2142] a hydrogen atom,

[2143] an alkyl group,

[2144] a hydroxyl group protected with a methoxymethyl,tetrahydropyranyl or the like group,

[2145] a hydroxyalkyl group protected with a methoxymethyl,tetrahydropyranyl or the like group,

[2146] an alkoxyl group,

[2147] an alkoxyalkyl group,

[2148] a dialkoxyalkyl group,

[2149] a dialkylamino group,

[2150] a monoalkylamino group having an amino group protected with atertiary butoxycarbonyl group,

[2151] a dialkylaminoalkyl group,

[2152] a monoalkylaminoalkyl group having an amino group protected witha tertiary butoxycarbonyl group,

[2153] a dialkylaminocarbonyl group,

[2154] a dialkylaminocarbonylalkyl group,

[2155] a dialkylaminoalkyloxy group,

[2156] a monoalkylaminoalkyloxy group having an amino group protectedwith a tertiary butoxycarbonyl group,

[2157] a dialkylaminocarbonylalkyloxy group or the like; and Q^(3c)represents any one of the following groups:

[2158] (wherein when the carbon atom to which R²³, R²⁴, R²⁵ or R²⁶ hasbeen bonded is not adjacent to the nitrogen atom, R²³, R²⁴, R²⁵ and R²⁶each independently represents:

[2159] a hydrogen atom,

[2160] an alkyl group,

[2161] a hydroxyl group protected with a methoxymethyl,tetrahydropyranyl or the like group,

[2162] a hydroxyalkyl group protected with a methoxymethyl,tetrahydropyranyl or the like group,

[2163] an alkoxyl group,

[2164] an alkoxyalkyl group,

[2165] a dialkoxyalkyl group,

[2166] a dialkylamino group,

[2167] a monoalkylamino group in which the amino moiety has beenprotected with a tertiary butoxycarbonyl group,

[2168] a dialkylaminoalkyl group,

[2169] a monoalkylaminoalkyl group having an amino group protected witha tertiary butoxycarbonyl group,

[2170] a dialkylaminocarbonyl group,

[2171] a dialkylaminocarbonylalkyl group,

[2172] a dialkylaminoalkyloxy group, or the like.

[2173] R²³ and R²⁴, as well as R²⁵ and R²⁶, may be coupled together toform a saturated or unsaturated 5- to 7-membered cyclic hydrocarbongroup which may have a substituent or a saturated or unsaturated 5- to7-membered heterocyclic group which may have a substituent.

[2174] R²⁷ represents:

[2175] an alkyl group,

[2176] a hydroxyalkyl group having the hydroxyl group protected,

[2177] a hydroxyalkylcarbonyl group having the hydroxyl group protected,

[2178] a hydroxyalkylsulfonyl having the hydroxyl group protected,

[2179] an alkoxyalkyl group,

[2180] an alkoxyalkylcarbonyl group,

[2181] an alkoxyalkylsulfonyl group,

[2182] an alkylcarbonyl group,

[2183] an alkylcarbonylalkyl group,

[2184] an alkylsulfonyl group,

[2185] an alkylsulfonylalkyl group,

[2186] an alkoxycarbonyl group,

[2187] an alkoxycarboylalkyl group,

[2188] an alkoxycarbonylalkylcarbonyl group,

[2189] an alkoxycarbonylalkylsulfonyl group,

[2190] a dialkylaminoalkyl group,

[2191] a monoalkylaminoalkyl group having the amino group protected witha tertiary butoxycarbonyl group,

[2192] a dialkylaminocarbonyl group,

[2193] a dialkylaminocarbonylalkyl group, or the like.

[2194] R²⁵ and R²⁷, or R²⁶ and R²⁷ may be coupled together to form asaturated or unsaturated 5- to 7-membered heterocyclic group which mayhave a substituent.

[2195] R²⁸ represents a tertiary butoxycarbonyl, benzyl ortriphenylmethyl group which means a protecting group of the nitrogenatom, j and k each independently represents an integer of 0 or 1 and 1stands for an integer of 1 to 3 with the proviso that the sum of k and lstands for an integer of 1 to 4.)]

[2196] The compound represented by the formula (VIIIa-1c) can beobtained by reacting an amino compound which is available by the knownprocess or application thereof and is represented by the followingformula (IIIb):

Q^(3c)-H  (IIIB)

[2197] [wherein Q^(3c) has the same meaning as described above] with analkylsulfonic acid halide in the presence of an appropriate base;reacting the resulting sulfonamide represented by the following formula(IXa):

[2198] [wherein R¹⁷ and Q^(3c) have the same meanings as describedabove] with a carbonyl compound represented by the following formula(XIa):

[2199] [wherein R¹⁶, R¹⁸, R¹⁹, R²², X¹ and X² have the same meanings asdescribed above] in an inert solvent in the presence of an appropriatebase to obtain the corresponding alcohol product represented by thefollowing formula (XIIa):

[2200] [wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²², Q^(3c), X¹ and X² have the samemeanings as described above]; converting the alcohol moiety of thealcohol product (XIIa) into a methanesulfonyloxy group or the like inthe presence of an appropriate base, or converting the alcohol moietyinto a halogen atom by using a phosphorus halide ortriphenylphosphine/carbon tetrahalide, thereby forming an eliminatinggroup; and then eliminating methanesulfonic acid or hydrogen halide inthe presence of an appropriate base.

[2201] The sulfonamide compound of the formula (IXa) can be obtained byreacting the amino compound of the formula (IIIb), which is available ina known process or by application thereof, with an alkylsulfonic halidewhich may have a substituent, in the presence of an appropriate base, inan inert solvent at −78 to 150° C.

[2202] Examples of the base include carbonates of an alkali metal oralkaline earth metal, such as sodium carbonate and potassium carbonateand organic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

[2203] Examples of the inert solvent include dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidin-2-one. Dimethylsulfoxide, sulfolane, acetone or thelike can be used, though depending on the kind of the base employed.

[2204] The alcohol compound of the formula (XIIa) can be obtained byreacting the sulfonamide of the formula (IXa) with a carbonyl compoundof the formula (XIa) in the presence of an appropriate base in an inertsolvent at −78 to 110° C.

[2205] Examples of the base include hydrides of an alkali metal oralkaline earth metal such as sodium ethoxide, potassium botoxide, sodiumhydride and potassium hydride; organometallic base compounds typified byalkyl lithium such as n-butyl lithium and dialkylaminolithium such aslithium diisopropylamide; organometallic base of bissilylamine compoundssuch as lithium bis(trimethylsilyl)amide. Examples of the inert solventinclude tetrahydrofuran, 1,2-dimethoxyethane and dioxane.

[2206] The compound of the formula (VIIIa-1c) can be obtained bytreating the hydroxyl group of the alcohol product of the formula (XIIa)with a phosphorus halide such as phosphorus pentachloride or atriphenylphosphine-halogen complex such as triphenylphosphine dibromideat −20 to 110° C., if necessary in the presence of an appropriate base,for example, the carbonate of an alkali metal or alkaline earth metal,such as sodium carbonate or potassium carbonate, or an organic base suchas pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine ordiazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such asdichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran,1,2-dimethoxyethane, dioxane, toluene or N,N-dimethylformamide, therebyobtaining the corresponding halide, and then eliminating the hydrogenhalide from the resulting halide under basic conditions, for example, bytreating at −78 to 150° C. with a carbonate, alkoxide, hydroxide orhydride of an alkali metal or alkaline earth metal, such as sodiumcarbonate, potassium carbonate, sodium ethoxide, potassium butoxide,sodium hydroxide, potassium hydroxide, sodium hydride or potassiumhydride, an organometallic base compound typified by alkyl lithium suchas n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide, an organometallic base of bissilylamine compound suchas lithium bis(trimethylsilyl)amide, or an organic base such aspyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane, chloroform,carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane,toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide.

[2207] The compound of the formula (VIIIa-1c) can also be obtained bytreating the hydroxyl group of the alcohol product represented by theformula (XIIa) with an alkyl- or arylsulfonic acid chloride such asmethanesulfonic acid chloride in the presence of an appropriate base,for example, a carbonate of an alkali metal or alkaline earth metal suchas sodium carbonate or potassium carbonate or an organic base such aspyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine ordiazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such asdichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran,1,2-dimethoxyethane, dioxane, toluene or N,N-dimethylformamide at −20 to110° C. to obtain the corresponding alkyl- or arylsulfonate derivative;and then eliminating the alkyl- or arylsulfonic acid from the resultingalkyl- or arylsulfonate derivative under basic conditions.

[2208] Described specifically, the compound of the formula (VIIIa-1c)can be obtained by treating the resulting alkylor arylsulfonatederivative at −78 to 150° C. in the presence of a carbonate, alkoxide,hydroxide or hydride of an alkali metal or alkaline earth metal such assodium carbonate, potassium carbonate, sodium ethoxide, potassiumbutoxide, sodium hydroxide, potassium hydroxide, sodium hydride orpotassium hydride, an organometallic base compound typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide, an organometallic base of bissilylamine compound suchas lithium bis(trimethylsilyl)amide, or an organic base such aspyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine ordiazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane, chloroform,carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane,toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide.

[2209] The compound of the formula (VIIIa-1c) can also be obtained bytreating the sulfonamide of the formula (IXa) with a silyl halide suchas trimethylsilyl chloride in the presence of an appropriate base in aninert solvent to convert it to the corresponding silyl compound,reacting the resulting silyl compound with a carbonyl compound of theformula (XIa) in the presence of a base in an inert solvent and thentreating the reaction product under acidic to basic aqueous conditions(Peterson's reaction).

[2210] Described specifically, the compound of the formula (VIIIa-1c)can be obtained by treating the sulfonamide of the formula (IXa) with analkylsilyl chloride such as trimethylsilyl chloride at −78 to 110° C. inthe presence of an alkoxide or hydride of an alkali metal or alkalineearth metal such as sodium ethoxide, potassium butoxide, sodium hydrideor potassium hydride, an organometallic base compound typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide, or an organometallic base of bissilylamine compoundsuch as lithium bis(trimethylsilyl)amide in a solvent such astetrahydrofuran, 1,2-dimethoxyethane or dioxane, to convert it to thecorresponding silyl compound, condensing with the carbonyl compound ofthe formula (XIa) under the same conditions and then treating thecondensate under acidic to basic aqueous conditions.

[2211] The protecting group of the nitrogen atom of the compoundrepresented by the formula (VIIIa-1c) can be removed by the ordinarilyemployed process. Described specifically, when the protecting group is atertiary butoxycarbonyl group, it can be removed by using an appropriateacid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonicacid or combination thereof. An arylmethyl group such as benzyl can beremoved by the hydrogenolysis in the presence of a palladium-carboncatalyst. A triphenylmethyl group can be removed by using an appropriateacid such as formic acid, acetic acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid or combination thereof. It can also beremoved by Birch reduction with a metal sodium in liquid ammonia or byhydrogenolysis in the presence of a palladium-carbon catalyst. Thus, bythe removal of the protecting group, the compound of the formula(VIIIa-1c) can be obtained.

[2212] <Synthesis of the Compound Represented by the Formula (VIIIa-2a)>

[2213] Among the compounds represented by the formula (VIIIa), thecompound of the formula (VIIIa-2a):

[2214] [wherein X³, X⁴, X⁵, X⁶, X⁷, X⁸ and Q^(3a) have the same meaningsas described above] can be synthesized by the following process.

[2215] Described specifically, the compound of the following formula(VIIIa-2b):

[2216] [wherein X³, X⁴, X⁵, X⁶, X⁷, X⁸ and Q^(3b) have the same meaningsas described above] can be obtained by sulfonylating the nitrogen atomof the primary or secondary amine or amide of the compound of theformula (IIIa):

Q^(3b)-H  (IIIa)

[2217] [wherein Q^(3b) has the same meaning as described above] with asulfonic acid halide represented by the following formula (IIa-2a):

[2218] [wherein X³, X⁴, X⁵, X⁶, X⁷, X⁸ and Halo have the same meaningsas described above] in the presence of an appropriate base in an inertsolvent at −78 to 150° C.

[2219] Specific examples of the base include carbonates, alkoxides,hydroxides and hydrides of an alkali metal or alkaline earth metal, suchas sodium carbonate, potassium carbonate, sodium ethoxide, potassiumbutoxide, sodium hydroxide, potassium hydroxide, sodium hydride andpotassium hydride; organometallic base compounds typified by alkyllithium such as n-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bissilylamine compounds such aslithium bis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2220] Examples of the inert solvent include dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and acetone.

[2221] When the nitrogen atom of Q^(3b) of the resulting compoundrepresented by the formula (VIIIa-2b) has been protected, the compoundof the formula (VIIIa-2a) can be obtained by carrying out deprotectionas needed.

[2222] Alternatively, the compound of the formula (VIIIa-2a) can beobtained by removing, as needed in an appropriate manner, the protectinggroup of the nitrogen atom of Q^(3d) from the compound which isavailable by the below-described preparation process and is representedby the following formula (VIIIa-2c):

[2223] [wherein X³, X⁴, X⁵, X⁶, X⁷ and X⁸ have the same meanings asdescribed above and Q^(3d) means any one of the following groups:

[2224] (wherein, when the carbon atom to which each of R³⁰, R³¹, R³² andR³³ has been bonded is not adjacent to a nitrogen atom, R³⁰, R³¹, R³²and R³³ each independently represents

[2225] a hydrogen atom,

[2226] an alkyl group,

[2227] a hydroxyl group,

[2228] a hydroxyl group protected with a methoxymethyl ortetrahydropyranyl or the like group,

[2229] a hydroxyalkyl group,

[2230] a hydroxyalkyl group having a hydroxyl group protected with amethoxymethyl or tetrahydropyranyl or the like group,

[2231] an alkoxyl group,

[2232] an alkoxyalkyl group,

[2233] a dialkoxyalkyl group,

[2234] a dialkylamino group,

[2235] a monoalkylamino group having an amino group protected with atertiary butoxycarbonyl group,

[2236] a dialkylaminoalkyl group,

[2237] a monoalkylaminoalkyl group having an amino group protected witha tertiary butoxycarbonyl group,

[2238] a dialkylaminocarbonyl group,

[2239] a dialkylaminocarbonylalkyl group,

[2240] a dialkylaminoalkyloxy group,

[2241] a monoalkylaminoalkyloxy group having an amino group protectedwith a tertiary butoxycarbonyl group,

[2242] a monoalkylaminocarbonylalkyloxy group having an amino groupprotected with a tertiary butoxycarbonyl group,

[2243] a dialkylaminocarbonylalkyloxy group,

[2244] a dialkylaminoalkyloxy group,

[2245] a monoalkylaminoalkyloxy group having an amino group protectedwith a tertiary butoxycarbonyl group,

[2246] a carbamoyl group,

[2247] a monoalkylcarbamoyl group,

[2248] a dialkylcarbamoyl group,

[2249] a carbamoylalkyl group,

[2250] a monoalkylcarbamoylalkyl group,

[2251] a dialkylcarbamoylalkyl group,

[2252] a pyrrolidinocarbonyl group,

[2253] a pyrrolidinocarbonylalkyl group,

[2254] a piperidinocarbonyl group,

[2255] a piperidinocarbonylalkyl group,

[2256] a morpholinocarbonyl group,

[2257] a morpholinocarbonylalkyl group,

[2258] a dialkylaminocarbonylalkyloxy group, or the like; when thecarbon atom to which each of R³⁰, R³¹, R³² and R³³ has been bonded isadjacent to a nitrogen atom, R³⁰, R³¹, R³² and R³³ each independentlyrepresents

[2259] a hydrogen atom,

[2260] an alkyl group,

[2261] a hydroxyalkyl group having a hydroxy group protected with amethoxymethyl, tetrahydropyranyl or the like group,

[2262] an alkoxyalkyl group,

[2263] a dialkoxyalkyl gorup,

[2264] a dialkylaminoalkyl group,

[2265] a monoalkylaminoalkyl group having an amino group protected witha tertiary butoxycarbonyl group,

[2266] a dialkylaminocarbonyl group,

[2267] a dialkylaminocarbonylalkyl group,

[2268] a carbamoyl group,

[2269] a monoalkylcarbamoyl group,

[2270] a carbamoylalkyl group,

[2271] a monoalkylcarbamoylalkyl group,

[2272] a pyrrolidinocarbonyl group,

[2273] a pyrrolidinocarbonylalkyl group,

[2274] a piperidinocarbonyl group,

[2275] a piperidinocarbonylalkyl group,

[2276] a morpholinocarbonyl group,

[2277] a morpholinocarbonylalkyl group,

[2278] a dialkylaminoalkyloxyalkyl group or the like;

[2279] R³⁰ and R³¹, or R³² and R³³ may be coupled together to form asaturated or unsaturated 5- to 7-membered cyclic hydrocarbon group whichmay have a substituent or a saturated or unsaturated 5- to 7-memberedheterocyclic group which may have a substituent;

[2280] R³⁴ represents

[2281] an alkyl group,

[2282] a hydroxyalkyl group having a protected hydroxyl group,

[2283] a hydroxyalkylcarbonyl group having a protected hydroxyl group,

[2284] a hydroxyalkylsulfonyl group having a protected hydroxyl group,

[2285] an alkoxyalkyl group,

[2286] an alkoxyalkylcarbonyl group,

[2287] an alkoxyalkylsulfonyl group,

[2288] an alkylcarbonyl group,

[2289] an alkylcarbonylalkyl group,

[2290] an alkylsulfonyl group,

[2291] an alkylsulfonylalkyl group,

[2292] an alkoxycarbonyl group,

[2293] an alkoxycarbonylalkyl group,

[2294] an alkoxycarbonylalkylcarbonyl group,

[2295] an alkoxycarbonylalkylsulfonyl group,

[2296] a dialkylaminoalkyl group,

[2297] a monoalkylaminoalkyl group having an amino group protected witha tertiary butoxycarbonyl group,

[2298] a dialkylaminocarbonyl group,

[2299] a dialkylaminocarbonylalkyl group or the like;

[2300] R³² and R³⁴, or R³³ and R³⁴ may be coupled together to form asaturated or unsaturated 5- to 7-membered heterocyclic group which mayhave a substituent;

[2301] R³⁵ represents an ordinarily employed protecting group for anitrogen atom such as tertiary butoxycarbonyl group, benzyl group ortriphenylmethyl group; j and k independently represents 0 or an integerof 1; and 1 stands for an integer of 1 to 3 with the proviso that thesum of k and 1 stands for an integer of 1 to 4)].

[2302] The compound represented by the following formula (VIIIa-2d):

[2303] [wherein X³, X⁴, X⁵, X⁶, X⁷, X⁸ and Q^(3d) have the same meaningsas described above] can be obtained by reacting an amino compound, whichis available in a known manner or by application thereof and isrepresented by the following formula (IIIc):

Q^(3d)-H  (IIIc)

[2304] [wherein Q^(3d) has the same meaning as described above] with afused heterocyclic thiol compound represented by the following formula(IIa-2e):

[2305] [wherein X³, X⁴, X⁵, X⁶, X⁷ and X⁸ have the same meanings asdescribed above] in the presence of an appropriate base and oxidizingagent.

[2306] The compound of the formula (VIIIa-2c) can be obtained byoxidizing the resulting compound of the formula (VIIIa2d) in an inertsolvent in the presence of an appropriate base.

[2307] The compound of the formula (VIIIa-2d) can be obtained byreacting an amino compound, which is represented by the formula (IIIc)and is available in a known manner or by application thereof, with athiol represented by the formula (IIa-2e) at −10 to 50° C. in thepresence of an appropriate base and oxidizing agent in water, an alcoholor dioxane or a mixed solvent thereof.

[2308] Examples of the base include carbonates and hydroxides of analkali metal or alkaline earth metal such as sodium carbonate, potassiumcarbonate, sodium hydroxide and potassium hydroxide. Examples of theoxidizing agent include oxygen, chlorine, bromine, iodine andhypochlorous acid. The compound of the formula (VIIIa-2c) can beobtained by reacting the resulting compound of the formula (VIIIa-2d)with an inorganic oxidizing agent such as potassium permanganate orhydrogen peroxide or an organic oxidizing agent such as3-chloroperbenzoic acid at −30° C. to 60° C. in the presence of anappropriate base in water, alcohol or a mixed solvent thereof.

[2309] The protecting group of the nitrogen atom can be removed from thecompound of the formula (VIIIa-2c) by an ordinarily employed process.Described specifically, when the nitrogen has been protected with atertiary butoxycarbonyl group, the protecting group can be removed usingan appropriate acid, for example, acetic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acidor trifluoromethanesulfonic acid or combination thereof. An arylmethylgroup such as benzyl can be removed by hydrogenolysis in the presence ofa palladium-carbon catalyst. A triphenylmethyl group can be removedusing an appropriate acid such as formic acid, acetic acid, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroaceticacid or trifluoromethanesulfonic acid or combination thereof. Thearylmethyl group such as benzyl can also be removed by Birch reduction,in liquid ammonia, in the presence of a metal sodium or byhydrogenolysis in the presence of a palladium-carbon catalyst. Bydeprotection as described above, the compound represented by the formula(VIIIa-2-a) can be obtained.

[2310] Among the compounds represented by the formula (VIIIa-2a), thecompound of the following formula (VIIIa-2e):

[2311] (wherein X³, X⁴, X⁵, X⁶, X⁷, X⁸, R¹⁰¹ and Q^(3a) have the samemeanings as described above] can also be obtained by removing theprotecting group of the nitrogen atom from Q^(3d) of the compound whichis available by the below-described preparation process and isrepresented by the formula (VIIIa-2f).

[2312] Described specifically, the compound of the following formula(VIIIa-2f):

[2313] [wherein X⁵, X⁶, X⁷, X⁸, R¹⁰¹ and Q^(3d) have the same meaningsas described above] can be obtained by reacting an amino compound whichis available in a known manner or by the application thereof and isrepresented by the following formula (IIIc):

Q^(3d)-H  (IIIc)

[2314] [wherein Q^(3d) has the same meaning as described above] with anacid halide represented by the following formula (IIa-2c):

[2315] [wherein X⁵, X⁶, X⁷, X⁸, R¹⁰¹ and Halo have the same meanings asdescribed above].

[2316] The compound of the formula (VIIIa-2f) can be obtained byreacting the compound of the formula (IIa-2e) with halogen such aschlorine gas at 0 to 30° C. for 10 minutes to 60 hours in water or amixed solvent of water with an organic carboxylic acid such as aceticacid, thereby forming the corresponding sulfonyl chloride; and thenadding the resulting sulfonyl chloride to an amino compound of theformula (IIIc), which has been dissolved in an appropriate solvent, at−50 to 40° C.

[2317] The reaction between the compound of the formula (IIa-2e) andhalogen is carried out at 0 to 20° C., usually in water or a 10 to 90%aqueous solution of acetic acid, if necessary in the presence of a Lewisacid such as ferric chloride as a catalyst. As the halogen, a chlorinegas is used. The reaction of the resulting acid chloride (IIa-2c) withthe amine of the formula (IIIc) is carried out at −20 to 50° C., ifnecessary in the presence of a base, in a solvent, for example, water,an alcohol solvent such as ethanol, an ether solvent such as diethylether, tetrahydrofuran, dimethoxyethane or dioxane, a halogen solventsuch as dichloromethane or chloroform or acetone or a mixed solventthereof, whereby the compound of the formula (VIIIa-2f) can be obtained.

[2318] Specific examples of the base include carbonates, alkoxides andhydroxides of an alkali metal or alkaline earth metal, such as sodiumcarbonate, potassium carbonate, sodium hydroxide and potassiumhydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

[2319] The protecting group of the nitrogen atom of the compoundrepresented by the formula (VIIIa-2f) can be removed by the ordinarilyemployed process. Described specifically, when the protecting group is atertiary butoxycarbonyl group, it can be removed by using an appropriateacid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonicacid or combination thereof. An arylmethyl group such as benzyl can beremoved by the hydrogenolysis in the presence of a palladium-carboncatalyst. A triphenylmethyl group can be removed by using an appropriateacid such as formic acid, acetic acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid or combination thereof. The arylmethylgroup such as benzyl group can also be removed by Birch reduction with ametal sodium in liquid ammonia or by hydrogenolysis in the presence of apalladium-carbon catalyst. Thus, by the removal of the protecting group,the compound of the formula (VIIIa-2e) can be obtained.

[2320] <Synthesis of the Compound of the Formula (VIIIa-3a)>

[2321] Among the compounds of the formula (VIIIa), the compound of thefollowing formula (VIIIa-3a):

[2322] [wherein X⁹, X¹⁰, X¹¹, X¹², Q^(3a), w and z have the samemeanings as described above] can be obtained by removing the protectinggroup from the nitrogen atom of Q^(3d) of the compound which isavailable by the below-described preparation process and is representedby the following formula (VIIIa3b)

[2323] [wherein X⁹, X¹⁰, X¹¹, X¹², Q^(3d), w and z have the samemeanings as described above].

[2324] Described specifically, the compound represented by the followingformula (XIV):

Q^(3d)-SO₂NHCOOR⁶⁰  (XIV)

[2325] [wherein R⁶⁰ and Q^(3d) have the same meanings as describedabove] can be synthesized by reacting an amino compound represented bythe following formula (IIIc):

Q^(3d)-H  (IIIc)

[2326] [wherein Q^(3d) has the same meaning as described above] with acompound represented by the following formula (XIII):

Cl—SO₂—NHCOOR⁶⁰  (XIII)

[2327] [wherein R⁶⁰ represents an easily removable group such astertiary butyl, benzyl, paramethoxybenzyl or paranitrobenzyl], which hasbeen obtained from chlorosulfonyl isocyanate and an alcohol, in thepresence of an appropriate base in an inert solvent.

[2328] The compound of the formula (VIIIa-3b) can be synthesized byremoving the protecting group from the nitrogen atom of the compound ofthe formula (XIV), thereby obtaining the compound represented by thefollowing formula (XV):

Q^(3d)-SO₂—NH₂  (XV)

[2329] [wherein, Q^(3d) has the same meaning as described above] andthen reacting the resulting compound of the formula (XV) with a compoundrepresented by the following formula (IIa-3a):

[2330] [wherein, X⁹, X¹⁰, X¹¹, X¹², w and z have the same meanings asdescribed above, L² and L³ each independently represents an eliminatinggroup frequently employed in organic chemistry such as chlorine,bromine, iodine, methylsufonyloxy or paratoluenesulfonyloxy] in thepresence of an appropriate base in an inert solvent.

[2331] The reaction between the compounds of the formula (IIIc) and(XIII) is carried out at −70 to 100° C. in an solvent, for example, anether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane ordioxane, a halogen solvent such as dichloromethane or chloroform,benzene, toluene or acetone, or a mixed solvent thereof in the presenceof a base such as sodium carbonate, potassium carbonate, or an organicbase such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU), whereby the compound of theformula (XIV) can be obtained.

[2332] The protecting group on the nitrogen atom of the compoundrepresented by the formula (XIV) can be removed as described below. Whenthe protecting group is a tertiary butoxycarbonyl group, it can beremoved using an appropriate acid such as acetic acid, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroaceticacid or trifluoromethanesulfonic acid, or combination thereof. Anarylmethyl group such as benzyloxycarbonyl, paranitrobenzyloxycarbonylor paramethoxybenzyloxycarbonyl can be removed by the hydrogenolysis inthe presence of a palladium-carbon catalyst. Theparamethoxybenzyloxycarbonyl group can be removed using an appropriateacid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonicacid or combination thereof. Thus, by the removal of the protectinggroup, the compound of the formula (XV) can be obtained.

[2333] The reaction of the compound of the formula (XV) with thecompound of the formula (IIa-3a) is carried out at −20 to 150° C. in thepresence of a base in a solvent, for example, an alcohol solvent such asethanol, an ether solvent such as diethyl ether, tetrahydrofuran,dimethoxyethane or dioxane, a halogen solvent such as dichloromethane orchloroform, a solvent such as acetone, or an amide solvent such asN,N-dimethylformamide, N-methylpyrolidin-2-one or acetamide, or a mixedsolvent thereof, whereby the compound of the formula (VIII-3b) can beobtained. Examples of the base include sodium carbonate, potassiumcarbonate, sodium hydride, potassium hydride, and organic bases such aspyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2334] The protecting group of the nitrogen atom of the compoundrepresented by the formula (VIII-3b) can be removed by the ordinarilyemployed process. Described specifically, when the protecting group is atertiary butoxycarbonyl group, it can be removed using an appropriateacid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonicacid or combination thereof. An arylmethyl group such as benzyl can beremoved by the hydrogenolysis in the presence of a palladium-carboncatalyst. A triphenylmethyl group can be removed using an appropriateacid such as formic acid, acetic acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid or combination thereof. The arylmethylgroup such as benzyl can also be removed by Birch reduction with a metalsodium in liquid ammonia or by hydrogenolysis in the presence of apalladium-carbon catalyst. Thus, by the removal of the protecting group,the compound of the formula (VIII-3a) can be obtained.

[2335] <Reaction of Any One of the Compounds of the Formulas (IVa) to(IVd) with the Compound of the Formula (VIIIa>

[2336] Examples of the carboxylic acid of each of the formulas (IVa) to(IVd) in an appropriate activated form include acid mixed acidanhydrides available by reacting the carboxylic acid of each of theformulas (IVa) to (IVd) with a chloroformate ester such as isobutylchloroformate, thereby converting it into the corresponding acidanhydride, acid halides such as acyl chloride prepared by treating withan inorganic acid halide such thionyl chloride, active esters obtainedby reacting with a phenol such as paranitrophenol orpentafluorophenyl-trifluoroacetate, active esters obtained by reactingit with N-hydroxybenztriazole or N-hydroxysuccinimide, reaction productswith N,N′-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride which isordinarily employed in the synthesis of an amino acid, reaction productswith diethyl cyanophosphonate (Shioiri's method) and reaction productswith triphenylphosphine and 2,2′-dipyridylsulfide (Mukaiyama's method).

[2337] The resulting carboxylic acid in an activated form is reactedwith the compound of the formula (VIIIa) at −78 to 150° C., usually inthe presence of an appropriate base in an inert solvent, whereby thesulfonyl derivative of the formula (I) can be obtained.

[2338] Examples of the base include carbonates, alkoxides, hydroxidesand hydrides of an alkali metal or alkaline earth metal, such as sodiumcarbonate, potassium carbonate, sodium ethoxide, potassium butoxide,sodium hydroxide, potassium hydroxide, sodium hydride and potassiumhydride; organometallic base compounds typified by alkyl lithium such asn-butyl lithium and dialkylaminolithium such as lithiumdiisopropylamide; organometallic base of bissilylamine compounds such aslithium bis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2339] Examples of the inert solvent include dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulfoxide and sulfolane.

[2340] [Preparation Process-2-(1)]

[2341] When the nitrogen atom of Q^(3a) of the compound represented bythe below-described formula (VIIIa) to be acylated:

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2342] [wherein, Q^(3a) and Q^(A) have the same meanings as describedabove] is a primary or secondary amine, preferred examples of the baseinclude carbonates and hydroxides of an alkali metal or alkaline earthmetal, such as sodium carbonate, potassium carbonate, sodium hydroxideand potassium hydroxide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU) and usable examples of the solventinclude, in addition to inert solvents, alcohol solvents such as ethanoland butanol and ester solvents such as ethyl acetate.

[2343] [Preparation Process-2-(2)]

[2344] When the nitrogen atom of Q^(3a) of the compound represented bythe below-described formula (VIIIa) to be acylated:

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2345] [wherein Q^(3a) and Q^(A) have the same meanings as describedabove] forms an amide bond, examples of the base include alkoxides andhydrides of an alkali metal or alkaline earth metal such as sodiumethoxide, potassium butoxide, sodium hydride and potassium hydride;organometallic base compounds typified by alkyl lithium such as n-butyllithium and dialkylaminolithium such as lithium diisopropylamide;organometallic base of bissilylamine compounds such as lithiumbis(trimethylsilyl)amide; and organic bases such asdiazabicyclo[5.4.0]undec-7-ene (DBU). Examples of the inert solventinclude tetrahydrofuran, 1,2-dimethoxyethane, dioxane andN,N-dimethylformamide.

[2346] [Preparation Process-3]

[2347] A process for preparing, in the case the nitrogen atom of Q^(3a)of the compound represented by the following formula (VIIIa):

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2348] [wherein, Q^(3a) and Q^(A) have the same meanings as describedabove] constitutes an amide, the sulfonyl derivative of the presentinvention by alkylating the nitrogen atom of the formula (VIIIa) withany one of the compounds represented by the following formulas (Va) to(Vd):

Q¹-Q^(2b)-CHL¹R¹³  (Va)

Q¹-N-(R²⁰)—(CH₂)_(m1)—CHL¹R¹³  (Vb)

Q¹-O—(CH₂)_(m1)—CHL¹R¹³  (Vc)

Q¹-S—(CH₂)_(m1)—CHL¹R¹³  (Vd)

[2349] [wherein Q¹, Q^(2b), R¹³, R²⁰, m1 and L¹ have the same meaningsas described above].

[2350] When the nitrogen atom of Q^(3a) of the compound of the formula(VIIIa) is a nitrogen atom of an amide bond, the sulfonyl derivative ofthe formula (I) can be synthesized by alkylating the nitrogen atom ofQ^(3a) of the compound of the formula (VIIIa) with any one of thecompounds of the formulas (Va) to (Vd). Described specifically, thesulfonyl derivative (I) can be obtained by reacting the compound of theformula (VIIIa) with any one of the compounds of the formulas (Va) to(Vd) at −78 to 150° C. for 0.5 to 120 hours in the presence of anappropriate base in an inert solvent, thereby effecting alkylation ofthe nitrogen atom.

[2351] Examples of the base include alkoxides and hydrides of an alkalimetal or alkaline earth metal, such as sodium ethoxide, potassiumbutoxide, sodium hydride and potassium hydride; organometallic basecompounds typified by alkyl lithium such as n-butyl lithium anddialkylaminolithium such as lithium diisopropylamide; organometallicbase of bissilylamine compounds such as lithiumbis(trimethylsilyl)amide; and organic bases such asdiazabicyclo[5.4.0]undec-7-ene (DBU). Preferred examples of the inertsolvent include tetrahydrofuran, 1,2-dimethoxyethane, toluene, dioxaneand N,N-dimethylformamide.

[2352] [Preparation Process-4]

[2353] A process for preparing, in the case where the nitrogen atom ofQ^(3a) of the compound represented by the formula (VIIIa):

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2354] [wherein, Q^(3a) and Q^(A) have the same meanings as describedabove] exists as a primary or secondary amine, the sulfonyl derivative(I) by forming the corresponding imine with any one of the carbonylcompounds represented by the following formulas (VIa) to (VId):

Q¹-Q^(2b)-C(═O)R¹³  (VIa)

Q¹-N-(R²⁰)—(CH₂)_(m1)—C(═O)R¹³  (VIb)

Q¹-O— (CH₂)_(m1)—C(═O)R¹³  (VIc)

Q¹-S—(CH₂)_(m1)—C(═O)R¹³  (VId)

[2355] [wherein Q¹, Q^(2b), R¹³, R²⁰ and m1 have the same meanings asdescribed above], followed by reduction.

[2356] Described specifically, when the nitrogen atom of Q^(3a) of thecompound of the formula (VIIIa) exists as an amine, the sulfonylderivative of the formula (I) can be prepared by reacting the compoundof the formula (VIIIa) with any one of the carbonyl compounds of theformulas (VIa) to (VId) at −20 to 150° C. for 0.5 to 120 hours, usuallyin an inert solvent, if necessary in the presence of an organic acidsuch as acetic acid, a mineral acid such as hydrochloric acid or a Lewisacid such as aluminum chloride, thereby forming the corresponding imineand then hydrogenating the resulting imine with a boron hydride reducingagent such as sodium borohydride, sodium cyanoborohydride or sodiumtriacetoxyborohydride or a catalytic reduction catalyst such aspalladium-carbon in an inert solvent at 10 to 110° C. for 0.5 to 120hours.

[2357] Examples of the inert solvent include dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulfoxide and sulfolane.

[2358] [Preparation Process-5]

[2359] A process for reacting, in the case where Q^(3a) of the compoundrepresented by the following formula (VIIIa):

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2360] [wherein, Q^(3a) and Q^(A) have the same meanings as describedabove] exists as a primary or secondary amine, the compound of theformula (VIIIa) with any one of the primary-aminecontaining compoundsrepresented by the following formulas (VIIa) to (VIId):

Q¹-Q^(2b)-NH₂  (VIIa)

Q¹-N-(R²⁰)—(CH₂)_(m2)—NH₂  (VIIb)

Q¹-O—(CH₂)_(m2)—NH₂  (VIIc)

Q¹-S—(CH₂)_(m2)—NH₂  (VIId)

[2361] or a secondary-amine-containing compound represented by thefollowing formula (VIIe):

[2362] [in the above-described formulas, Q¹, Q^(2b), R²⁰, m2 and thegroup:

[2363] have the same meanings as described above] by using a reagentsuch as phosgene, triphosgene or carbonyldiimidazole, thereby formingthe corresponding urea derivative.

[2364] When Q^(3a) of the compound of the formula (VIIIa) exists as anamine, the compound of the formula (VIIIa) is reacted with any one ofthe primary-amine-containing compounds represented by the formulas(VIIa) to (VIId) or the secondaryamine-containing compound representedby the formula (VIIe) and the reagent such as phosgene, triphosgene or1,1′-carbonyldiimidazole to introduce it into the sulfonyl derivative ofthe present invention represented by the formula (I), which is to be anurea derivative.

[2365] The synthesis can be carried out by successively reacting, withthe reagent such as phosgene, triphosgene or 1,1′-carbonyldiimidazole,any one of the primary-amine-containing compounds of the formulas (VIIa)to (VIId) or the secondary-amine-containing compound of the formula(VIIe) and the compound of the formula (VIIIa), if necessary in thepresence of a base, in an inert solvent. Examples of the inert solventinclude dichloromethane, chloroform, carbon tetrachloride,tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulfoxide and sulfolane. Among them, dichloromethane,tetrahydrofuran and toluene are preferred.

[2366] Examples of the base include carbonates and hydroxides of analkali metal or alkaline earth metal such as sodium carbonate, potassiumcarbonate, sodium hydroxide and potassium hydroxide; and organic basessuch as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU). The reaction may be conducted at atemperature range of from −70° C. to 110° C.

[2367] [Preparation Process-6]

[2368] A process for preparing a urea-containing sulfonyl derivative ofthe formula (I) by reacting, in the case where the nitrogen atom ofQ^(3a) of the compound represented by the formula (VIIIa):

Q^(3a)-SO₂-Q^(A)  (VIIIa)

[2369] [wherein, Q^(3a) and Q^(A) have the same meanings as describedabove] exists as a primary or secondary amine, the amine of the formula(VIIIa) with a known isocyanate derivative (Q¹-Q^(2b)-N═C═O) [wherein,Q¹ and Q^(2b) have the same meanings as described above] or anisocyanate prepared from any one of the carboxylic acids represented bythe following formulas (IVa) to (IVd):

Q¹-Q^(2b)-COOH  (IVa)

Q¹-N-(R²⁰)—(CH₂)_(m1)—COOH  (IVb)

Q¹-O—(CH₂)_(m1)—COOH  (IVc)

Q¹-S—(CH₂)_(m1)—COOH  (IVd)

[2370] [wherein Q¹, Q^(2b), R²⁰ and m1 have the same meanings asdescribed above].

[2371] When Q^(3a) of the compound represented by the formula (VIIIa) isan amine, the sulfonyl derivative of the formula (I) can be prepared byreacting the compound of the formula (VIIIa) with a known isocyanatederivative at −20 to 100° C. for 0.5 to 120 hours in an inert solvent.

[2372] The isocyanate derivative can be synthesized from any one of thecarboxylic acids of the formulas (IVa) to (IVd).

[2373] Described specifically, it can be obtained by introducing any oneof the carboxylic acids of the formulas (IVa) to (IVd) into thecorresponding acid halide with thionyl chloride, oxalyl chloride or thelike, reacting the resulting acid halide with sodium azide at atemperature range of from 0 to 60° C. in an inert solvent and then,heating the reaction mixture; by reacting the carboxylic acid of theformula (IVa) with a chloroformate such as isobutyl chloroformate,reacting the resulting acid anhydride with sodium azide and then heatingthe reaction mixture; or introducing any one of the carboxylic acidsrepresented by the formulas (IVa) to (IVd) into the correspondinghydrazide through an ester in an inert solvent such as tetrahydrofuran,chloroform or toluene at −20 to 110° C., reacting the resulting hy20drazide with nitrous acid or alkyl ester thereof to introduce it intothe corresponding acylazide and then heating at 20 to 150° C. in asolvent such as chloroform, dichloroethane, toluene, xylene orN,N-dimethylformamide.

[2374] The sulfonyl derivative of the formula (I) can also be preparedby reacting any one of the carboxylic acids of the formulas (IVa) to(IVd) with diphenylphosphorylazide at 10 to 100° C. in the presence of abase such as triethylamine in an inert solvent.

[2375] [Preparation Process-7]

[2376] The compound represented by the following formula (XVI):

Q¹-Q²-T¹-Q³-SO₂—NHCOOR⁶⁰  (XVI)

[2377] [wherein, Q¹, Q², Q³, R⁶⁰ and T¹ have the same meanings asdescribed above] can be synthesized by reacting, in the case where thenitrogen atom of Q^(3a) of the compound represented by the followingformula (Ia) to be sulfonylated:

Q¹-Q²-T¹-Q^(3a)  (Ia)

[2378] [wherein, Q¹, Q², Q^(3a) and T¹ have the same meanings asdescribed above] exists as a primary or secondary amine, the compound ofthe formula (Ia) with a compound which is available from chlorosulfonylisocyanate and an alcohol and is represented by the following formula(XIII):

Cl—SO₂—NHCOOR⁶⁰  (XIII)

[2379] [wherein, R⁶⁰ has the same meaning as described above] in thepresence of an appropriate base in an inert solvent.

[2380] The compound represented by the following formula (I-3a):

[2381] [wherein, Q¹, Q², Q³, T¹, X⁹, X¹⁰, X¹¹, X¹², w and z have thesame meanings as described above], one of the compounds of the formula(I), can be synthesized by removing the protecting group on the nitrogenatom of the resulting compound (XVI), thereby obtaining a compoundrepresented by the following formula (XVII):

Q¹-Q²-T¹-Q³-SO₂—NH₂  (XVII)

[2382] [wherein, Q¹, Q², Q³ and T¹ have the same meanings as describedabove]; and then reacting the resulting compound of the formula (XVII)with a compound represented by the following formula (IIa-3a):

[2383] [wherein, X⁹, X¹⁰, X¹¹, X¹² L², L³, w and z have the samemeanings as described above] in an appropriate base in an inert solvent.

[2384] The reaction between the compound of the formula (Ia) and thecompound of the formula (XIII) to synthesize the compound of the formula(XVI) is effected at −70 to 100° C. in an solvent, for example, an ethersolvent such as diethyl ether, tetrahydrofuran, dimethoxyethane ordioxane, a halogen solvent such as dichloromethane or chloroform, or asolvent such as benzene, toluene or acetone or a mixed solvent thereofand in this reaction, usable examples of the base include sodiumcarbonate, potassium carbonate and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2385] The protecting group on the nitrogen atom of the compound of theformula (XVI) can be removed as described below. When the protectinggroup is a tertiary butoxycarbonyl group, it can be removed using anappropriate acid such as acetic acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid, or combination thereof. An arylmethylgroup such as benzyloxycarbonyl, paranitrobenzyloxycarbonyl orparamethoxybenzyloxycarbonyl can be removed by the hydrogenolysis in thepresence of a palladium-carbon catalyst. Theparamethoxybenzyloxycarbonyl group can be removed using an appropriateacid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonicacid or combination thereof. Thus, by the removal of the protectinggroup, the compound of the formula (XVII) can be obtained.

[2386] The reaction of the compound of the formula (XVII) with thecompound of the formula (IIa-3a) is carried out at −20 to 150° C. in thepresence of a base in a solvent, for example, an alcohol solvent such asethanol, an ether solvent such as diethyl ether, tetrahydrofuran,dimethoxyethane or dioxane, a halogen solvent such as dichloromethane orchloroform, a solvent such as acetone, N,N-dimethylformamide,N-methylpyrolidin-2-one or acetamide, or a mixed solvent thereof,whereby the compound of the for5 mula (I-3a), one of the compounds ofthe formula (I), can be obtained.

[2387] Examples of the base include sodium carbonate, potassiumcarbonate, and organic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

[2388] From the compound of the formula (1-3a), it is possible toeliminate the protecting group in an ordinarily employed process ifnecessary.

[2389] [Preparation Process-8]

[2390] A process for synthesizing a sulfonyl derivative represented bythe following formula (I):

Q¹-Q²-T¹-Q³-SO₂-Q^(A)  (I)

[2391] [wherein, Q¹, Q², Q³, Q^(A), T¹ have the same meanings asdescribed above] by coupling reaction using a transition metal catalyst.

[2392] When in the structure of Q¹ of the sulfonyl derivative of theformula (I), a halogen- or trifluoromethanesulfonyloxy-substituted arylgroup or a halogen- or trifluoromethanesulfonyloxy-substituted alkenylgroup is contained, it can be subjected to coupling reaction with aboric-acid-substituted aryl compound in the presence of a transitionmetal catalyst.

[2393] When in the structure of Q¹ of the sulfonyl derivative of theformula (I), an alkenyl group is contained, it can be subjected tocoupling reaction with a halogen- ortrifluoromethanesulfonyloxy-substituted aryl group in the presence of atransition metal catalyst.

[2394] When in the structure of Q¹ of the sulfonyl derivativerepresented by the formula (I), a boric-acid-substituted aryl group iscontained, it can be subjected to coupling reaction with a halogen- ortrifluoromethanesulfonyloxysubstituted aryl compound or a halogen- ortrifluoromethanesulfonyloxy-substituted alkenyl compound.

[2395] When in the structure of Q¹ of the sulfonyl derivative of theformula (I), a halogen- or trifluoromethanesulfonyloxy-substituted arylgroup or a halogen- or trifluoromethanesulfonyloxy-substituted alkenylgroup is contained, it can be subjected to coupling reaction with aboric-acid-substituted aryl derivative by using a transition metalcatalyst such as tetrakis(triphenylphosphine)palladium (O), in atwo-phase solvent such as benzene-water or toluene-water, an amidesolvent such as N,N-dimethylformamide or an ether solvent such astetrahydrofuran or dimethoxyethane, in the presence of a base such assodium carbonate, sodium hydroxide, barium hydroxide, potassiumphosphate or cesium carbonate or a neutral salt such as cesium fluorideat a temperature range of 20 to 150° C. for 0.5 to 120 hours.

[2396] When in the structure of Q¹ of the sulfonyl derivativerepresented by the formula (I), an alkenyl group orboricacid-substituted alkenyl group is contained, it can be subjected tocoupling reaction with a halogen- ortrifluoromethanesulfonyloxy-substituted aryl group by using a transitionmetal catalyst such as palladium acetate, in the presence of anappropriate base, in an amide solvent such as N,N-dimethylformamide at atemperature range of from 20 to 150° C. for 0.5 to 120 hours.

[2397] When in the structure of Q¹ of the sulfonyl derivativerepresented by the formula (I), halogen- ortrifluoromethanesulfonyloxy-substituted aryl group, it can be subjectedto coupling reaction with an alkenyl compound by using a transitionmetal catalyst. By the above-described process, the sulfonyl derivativeof the formula (I) can be obtained. From the sulfonyl derivative of theformula (I) can be obtained. By deprotection, the sulfonyl derivative ofthe formula (I) having a changed substituent can be obtained.

[2398] [Preparation Process-9]

[2399] A process for preparing each of a thioamido type sulfonamideproduct, an amidoxime type sulfonamide product and a hydrazono typesulfonamide product:

[2400] When T¹-Q³ of the sulfonyl derivative represented by thefollowing formula (I):

Q¹-Q²-T¹-Q³-SO₂-Q^(A)  (I)

[2401] [wherein Q¹, Q², Q³, Q^(A) and T¹ have the same meanings asdescribed above] represents any one of the following formulas:

[2402] [wherein R³, R⁴, R⁷, R⁸ and R⁹ have the same meanings asdescribed above, n stands for an integer of 1 or 2, p stands for aninteger of 1 to 3 and q stands for an integer of 0 to 3 with the provisothat the sum of p and q stands for an integer of 3 or 4] and none ofamine-, alkylamine-, amido-, hydroxyl- and carboxylic-acid-containingsubstituents exist on R³, R⁴, R⁷, R⁸, R⁹ or a substituent substitutabletherefor in Q¹, Q² and Q³ of the formula (I), a thioamido typesulfonamide derivative (I) can be obtained by reacting the sulfonylderivative represented by the formula (I) with a diphosphorouspentasufide or Lawson reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disufide) at−30 to 150° C., if necessary in an inert solvent at 0 to 120° C.Examples of the inert solvent include alkyl halide solvents such asdichloromethane, chloroform and carbon tetrachloride, ether solventssuch as tetrahydrofuran, 1,2-dimethoxyethane and dioxane and aromaticsolvents such as benzene and toluene, and a mixture thereof.

[2403] The sulfonamide derivative represented by the formula (I) can beobtained by reacting the obtained thioamido type sulfomide with ahydroxylamine, alkoxyamine which may have a substituent, and hydrazinewhich may have a substituent, or a salt thereof, in the presence of amercury catalyst such as a mercury (II) chloride at −30 to 150° C. ifnecessary, or in an appropriate solvent 0 to 120° C. if necessary.Examples of the solvent include alcohol solvents such as ethanol, alkylhalide solvents such as dichloromethane, chloroform and carbontetrachloride, ether solvents such as tetrahydrofuran,1,2-dimethoxyethane and dioxane and aromatic solvents such as benzeneand toluene, and a mixture thereof.

[2404] The sulfonyl derivative represented by the formula (I) can beobtained by reacting the sulfonyl derivative of the formula (I) with ahalogenating agent such as phosphorous oxychloride or phosphoruspentachloride or an alkylating agent such as Meerwein reagent at −30 to140° C., if necessary in an inert solvent, for example, a halogensolvent such as chloroform at 0 to 80° C., to convert the derivativeinto the corresponding imino chloride or imino ether and then, reactingthe resulting imino chloride or imino ether with hydroxylamine,alkoxyamine which may have a substituent or salt thereof at 0 to 80° C.,preferably at 20 to 60° C., if necessary in the presence of a basecatalyst.

[2405] Examples of the inert solvent include alkyl halide solvents suchas dichloromethane, chloroform and carbon tetrachloride, ether solventssuch as tetrahydrofuran, 1,2-dimethoxyethane and dioxane and aromaticsolvents such as benzene and toluene. Among them, the alkyl halidesolvents are particularly preferred. Examples of the base includecarbonates, alkoxides, hydroxides and hydrides of an alkali metal oralkaline earth metal, such as sodium carbonate, potassium carbonate,sodium ethoxide, potassium butoxide, sodium hydroxide, potassiumhydroxide, sodium hydride and potassium hydride; organometallic basecompounds typified by an alkyl lithium such as n-butyl lithium and adialkylamino lithium such as lithium diisopropylamide; organometallicbase of bissilylamine compounds such as lithiumbis(trimethylsilyl)amide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2406] [Preparation Process-10]

[2407] N-Oxide Formation

[2408] When in the sulfonyl derivative of the formula (I), there existsa nitrogen-containing heterocyclic aromatic ring or aliphatic tertiaryamine on Q¹, Q², Q³ Q^(A) or T¹ or a substituent substitutable therefor,the sulfonyl derivative of the formula (I) is reacted with a peroxidesuch as hydrogen peroxide, metachloroperbenzoic acid or tertiary butylhydroperoxide at −40 to 60° C. for 0.5 to 120 hours preferably −20 to20° C. in a solvent such as water, acetic acid, a benzene solvent suchas benzene, toluene or xylene, an ether solvent such as tetrahydrofuranor dimethoxyethane or an alkyl halide solvent such as dichloromethane,chloroform or carbon tetrachloride, whereby the sulfonyl derivative ofthe formula (I) can be obtained as an N-oxide derivative.

[2409] [Preparation Process-11]

[2410] Quaternization of a Nitrogen Atom

[2411] When in the sulfonyl derivative of the formula (I), there existsa nitrogen-containing heterocyclic aromatic group or aliphatic tertiaryamine on Q¹, Q², Q³, Q^(A) or T¹ or a substituent substitutabletherefor, the sulfonyl derivative of the formula (I) is reacted with analkyl halide such as methyl iodide or ethyl iodide in an ether solventsuch as 1,2-dimethoxyethane or dioxane, an aromatic solvent such asbenzene or toluene, an amide solvent such as N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidin-2-one or a sulfoxide solventsuch as dimethyl sulfoxide or sulfolane at −10 to 150° C., preferably 0to 80° C., whereby the sulfonyl derivative of the formula (I) can beobtained as a quaternary amino product.

[2412] [Preparation Process-12]

[2413] Sulfoxide or Sulfone Formation

[2414] When in the sulfonyl derivative of the formula (I), asulfur-containing hetero ring or aliphatic thioether exists on Q¹, Q²,Q³, Q^(A) or T¹ or a substituent substitutable therefor, the sulfonylderivative of the formula (I) is reacted with a peroxide such ashydrogen peroxide, metachloroperbenzoic acid or tertiary butylhydroperoxide at −40 to 60° C. for 0.5 to 120 hours, preferably −20 to20° C. in a solvent such as water or acetic acid, a benzene solvent suchas benzene, toluene or xylene, an ether solvent such as tetrahyuroluranor dimethoxyethane or an alkyl halide solvent such as dichloromethane,chloroform or carbon tetrachloride, whereby the sulfonyl derivative (I)can be obtained in the form of sulfoxide or sulfone.

[2415] [Preparation Process-13]

[2416] Amidino Formation-1

[2417] When in the sulfonyl derivative of the formula (I), a nitrilegroup exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituent substitutabletherefor, it can be converted into an amidino group by an ordinarilyemployed process. The amidino-containing sulfonyl derivative of theformula (I) can be obtained, for example, by allowing an equal amount tolarge excess of a C₁₋₄ alcohol such as methanol, ethanol or propanol toact on the sulfonyl derivative of the formula (I) at −10 to 60° C. for 3to 120 hours in an aliphatic ether solvent such as diethyl ether, analkyl halide solvent such as chloroform or dichloromethane or an aproticsolvent such as benzene or a mixed solvent thereof in the presence of ahydrogen halide such as hydrogen chloride or hydrogen bromide, therebyconverting it to the corresponding imino ether; then reacting theresulting imino ether product with ammonium, a monoalkylamine which mayhave a substituent or a dialkylamine which may have a substituent, or acarbonate or acetate thereof at −10 to 140° C. for 0.5 to 200 hours in aC₁₋₄ alcohol such as ethanol or propanol, an aliphatic ether solventsuch as diethyl ether, an alkyl halide solvent such as chloroform, anaprotic solvent such as benzene, a solvent such as N,N-dimethylformamideor dimethylsulfoxide or a mixed solvent thereof, preferably at −8 to 30°C. for 10 to 96 hours in ethanol.

[2418] [Preparation Process-14]

[2419] Amidino Formation-2

[2420] When in the sulfonyl derivative of the formula (I), a primary orsecondary amino group exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituentsubstitutable therefor, it can be converted into a substituted amidinogroup by an ordinarily employed process.

[2421] Described specifically, the amidino-containing sulfonylderivative of the formula (I) can be obtained, for example, by reactingthe sulfonyl derivative of the formula (I) with an imino ether, iminochloride or salt thereof, which has been synthesized from an amidecompound or nitrile compound, in an aliphatic ether solvent such asdiethyl ether, an alkyl halide solvent such as chloroform ordichloromethane or an aprotic solvent such as benzene, or a mixedsolvent thereof, if necessary in the presence of a base catalyst, at −10to 140° C. for 0.5 to 200 hours, preferably 0 to 80° C. for 10 to 96hours. Examples of the base include carbonates and hydroxides of analkali metal or alkaline earth metal, such as sodium carbonate,potassium carbonate, sodium hydroxide and potassium hydroxide andorganic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

[2422] [Preparation Process-15]

[2423] N-Nitrile Formation

[2424] When in the sulfonyl derivative of the formula (I), a primary orsecondary amine group exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituentsubstitutable therefor, it can be cyanated by an ordinarily employedprocess.

[2425] For example, the sulfonyl derivative of the formula (I) isreacted with cyan bromide in an alcohol solvent such as methanol,ethanol or propanol in the presence of a salt such as sodium acetate ora base at −10 to 110° C., preferably 0 to 60° C., whereby the sulfonylderivative (I) having a nitrile group on its nitrogen atom can beobtained. Examples of the base include carbonates and hydroxides of analkali metal or alkaline earth metal, such as sodium carbonate,potassium carbonate, sodium hydroxide and potassium hydroxide; andorganic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

[2426] [Preparation Process-16]

[2427] Amidoxime or Carboxamido-O-Alkyloxime Introduction

[2428] When in the sulfonyl derivative of the formula (I), a nitrilegroup exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituent substitutabletherefor, it can be converted into an amidoxime orcarboxamido-O-alkyloxime group by an ordinarily employed process.

[2429] For example, the sulfonyl derivative of the formula (I) isreacted with hydroxylamine or an alkoxyamine which may have asubstituent, or salt thereof in an alcohol solvent such as methanol,ethanol or propanol, an ether solvent such as diethyl ether ortetrahydrofuran, a halogenated hydrocarbon such as chloroform ordichloromethane, an aprotic solvent such as toluene, an amide solventsuch as N,N-dimethylformamide or a solvent such as dimethylsulfoxide, ora mixed solvent thereof at −10 to 110° C., preferably 0 to 60° C., ifnecessary in the presence of a base catalyst, whereby the sulfonylderivative of the formula (I) having an amidoxime orcarboxamido-O-alkyloxime group can be obtained. Examples of the baseinclude carbonates and hydroxides of an alkali metal or alkaline earthmetal such as sodium carbonate, potassium carbonate, sodium hydroxideand potassium hydroxide; and organic bases such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,N-methylmorpholine, diisopropylethylamine anddiazabicyclo[5.4.0]undec-7-ene (DBU).

[2430] [Preparation Process-17]

[2431] Guanidino Introduction

[2432] When in the sulfonyl derivative of the formula (I), a primary orsecondary amino group exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituentsubstitutable therefor, it can be converted into a substituted orunsubstituted guanidino group by an ordinarily employed process.

[2433] For example, the sulfonyl derivative of the formula (I) having aprimary or secondary amino group is reacted withN,N′-di(tert-butoxy)carbonylthiourea and N,N′-dicyclohexylcarbodiimideas a condensing agent in an aliphatic ether solvent such as diethylether, a halogenated hydrocarbon such as chloroform or dichloromethaneor an aprotic solvent such as benzene, or a mixed solvent thereof at −10to 140° C. for 0.5 to 200 hours, preferably 0 to 80° C. for 10 to 96hours, if necessary in the presence of a base catalyst, and then, asusual, the tertiary butoxycarbonyl group is removed, whereby thesulfonyl derivative of the formula (I) as a guanidino compound can besynthesized. Examples of the base include carbonates and hydroxides ofan alkali metal or alkaline earth metal, such as sodium carbonate,potassium carbonate, sodium hydroxide and potassium hydroxide; andorganic bases such as pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, N-methylmorpholine,diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).

[2434] [Preparation Process-18]

[2435] Deprotection from the Protected Nitrogen Atom

[2436] When in the sulfonyl derivative of the formula (I), an acylaminoor alkoxycarbonylamino group exists on Q¹, Q², Q³, Q^(A) or T¹ or asubstituent substitutable therefor, an aminocontaining derivative can beobtained by subjecting the derivative to hydrolysis at 0 to 80° C. in asolvent such as water, a lower alcohol or tetrahydrofuran, or a mixedsolvent thereof in the presence of a base such as an alkali metalhydroxide e.g. lithium hydroxide, sodium hydroxide or potassiumhydroxide. The nitrogen atom to which an acyl type protecting group suchas tertiary butoxycarbonyl or paramethoxybenzyloxycarbonyl has beenbonded can be converted into a nitrogen-hydrogen bond by using anappropriate acid such as acetic acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trifluoroacetic acid ortrifluoromethanesulfonic acid or combination thereof in a solvent suchas water, an alcohol solvent such as methanol, an alkyl halide solventsuch as dichloromethane, chloroform or carbon tetrachloride, an ethersolvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane or anaromatic solvent such as benzene or toluene and removing the acyl typeprotecting group from the nitrogen atom at 0 to 80° C.

[2437] The nitrogen atom to which an arylmethoxycarbonyl group such asbenzyloxycarbonyl, paramethoxybenzyloxycarbonyl orpara(ortho)-nitrobenzyloxycarbonyl has been bonded can be converted intoa nitrogen-hydrogen bond by removing the arylmethoxycarbonyl group fromthe protected nitrogen atom through hydrogenolysis in the presence of apalladium-carbon catalyst in a solvent such as water, an alcohol solventsuch as ethanol, an ester solvent such as ethyl acetate, an ethersolvent such as diethyl ether or tetrahydrofuran, or a solvent such asacetic acid or N,N-dimethylformamide, or a mixed solvent thereof. Thenitrogen atom to which a silyl type protecting group such astrimethylsilyl or tertiary butyl dimethylsilyl has been bonded can beconverted into a nitrogen-hydrogen bond by reacting with hydrochloricacid or a hydrofluoride such as tetrabutylammonium fluoride at 0 to 80°C. in an alkyl halide solvent such as dichloromethane, chloroform orcarbon tetrachloride, an ether solvent such as tetrahydrofuran,1,2-dimethoxyethane or dioxane or an aromatic solvent such as benzene ortoluene, thereby removing the silyl group from the protected nitrogenatom. The nitrogen atom to which a benzyl group has been bonded can beconverted into a nitrogen-hydrogen bond by removing the benzyl groupthrough the catalytic reduction at 0 to 80° C. with a palladium-carboncatalyst or the like in a solvent such as ethanol, tetrahydrofuran oracetic acid or through the Birch's reduction with a metal sodium in aliquid ammonia. The nitrogen atom to which a triphenylmethyl group hasbeen bonded can be converted into a nitrogen-hydrogen bond by removingthe triphenylmethyl group through the catalytic reduction with apalladium-carbon catalyst or the like at 0 to 80° C. in a solvent suchas ethanol, tetrahydrofuran or acetic acid or through the Birch'sreduction with a metal sodium in a liquid ammonia. The removal of thetriphenylmethyl group and conversion into a nitrogen-hydrogen bond canalso be carried out by using an appropriate acid, such as formic acid,acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid,or a combination thereof at 0 to 80° C.

[2438] [Preparation Process-19]

[2439] Ester Hydrolysis

[2440] When in the sulfonyl derivative of the formula (I), analkoxycarbonyl group exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituentsubstitutable therefor, in the case of a methyl or ethyl ester, thealkoxycarbonyl group can be converted into the corresponding carboxylicacid by the hydrolysis with an appropriate base, for example, an alkalimetal hydroxide such as lithium hydroxide, sodium hydroxide or potassiumhydroxide. In the case of a tertiary butyl ester, the tertiary butylgroup can be removed by treating with trifluoroacetic acid orhydrochloric acid, while in the case of an arylmethyl type ester such asbenzyl, the carboxylic acid can be obtained by removing the arylmethylgroup by hydrogenolysis in the presence of a palladiumcarbon catalyst.Conversion from an ester group to a carboxylic acid residue can beeffected using potassium trimethylsilanolate.

[2441] [Preparation Process-20]

[2442] When in the sulfonyl derivative of the formula (I), an acyloxy,arylmethyloxy, silylether, methoxymethyl or tetrahydropyranyl groupexists on Q¹, Q², Q³, Q^(A) or T¹ or a substituent substitutabletherefor, the acyl group such as alkanoyl or aroyl can be removed by thehydrolysis with an appropriate base, for example, an alkali metalhydroxide such as lithium hydroxide, sodium hydroxide or potassiumhydroxide; or alternatively can be removed by reacting with an organicbase such as ammonia or methylamine. The arylmethyl type protectinggroup can be removed by the hydrogenolysis with a palladium-carboncatalyst. The silylether group such as tertiary butyl dimethylsilyl canbe removed by a hydrofluoride salt such as tetrabutylammonium fluoride.The methoxymethyl or tetrahydropyranyl group can be removed using aceticacid or hydrochloric acid.

[2443] [Preparation Process-21]

[2444] When in the sulfonyl derivative of the formula (I), an aminogroup exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituent substitutabletherefor, it can be acylated by an ordinarily employed process whichuses an acyl halide or activated carboxylic acid. Alternatively, it canbe alkylated by reductive alkylation or the like process. The sulfonylderivative of the formula (I) which is an urea derivative can beprepared by sulfonylation through sulfonic acid chloride or by reactingwith isocyanate or carboxylic-acid-derived isocyanate.

[2445] [Preparation Process-22]

[2446] When in the sulfonyl derivative of the formula (I), an carboxylgroup exists on Q¹, Q², Q³, Q^(A) or T¹ or a substituent substitutabletherefor, it can be converted into a carbamoyl, alkylcarbamoyl ordialkylcarbamoyl group by an ordinarily employed active ester method ormixed acid anhydride method and then converted into a hydroxyl oraldehyde group by reduction. The resulting hydroxyl or aldehyde groupcan be subjected to conversion of a functional group, such as ether bondformation, conversion into an amino group or conversion into analkylamino group by the process ordinarily employed in organicchemistry. The carboxyl group, after conversion into its ester or mixedacid anhydride directly or by the usual process, is reduced, whereby thecorresponding alcohol can be obtained.

[2447] [Preparation-23]

[2448] Formation of Phenol

[2449] When in the sulfonyl derivative of the formula (I), anaryl-substituted methoxy group exists on Q¹, Q², Q³, Q^(A) or T¹ or asubstituent substitutable therefor, it can be converted into a hydroxylgroup by removing the methyl group using trimethylsilyl iodide at −78 to110° C. in an alkyl halide solvent such as dichloromethane, chloroformor carbon tetrachloride or a benzene solvent such as toluene, or at −78to 110° C. in a Lewis acid such as aluminum chloride, phosphorustribromide or boron trifluoride, an alkyl halide solvent or an ethersolvent.

[2450] [Preparation process-24]

[2451] Conversion of a Halogen Atom into an Alkynyl Group

[2452] When the compound of the formula (I), the compound of the formula(VIIIa), the compound of the formula (VIIIalb), the compound of theformula (VIIIa-1c), the compound of the formula (VIIIa-2a), the compoundof the formula (VIIIa-2b), the compound of the formula (VIIIa-2c), thecompound of the formula (VIIIa-2d), the compound of the formula(VIIIa-2e), the compound of the formula (VIIIa-3a), or the compound ofthe formula (VIIIa-3b) has an aromatic ring substituted with chlorine,bromine or iodine, such a halogen atom can be converted into anacetylene group by reacting with a silylacetylene compound in thepresence of a transition metal catalyst.

[2453] The conversion of chlorine, bromine or iodine into asilylacetylene group can be carried out by reacting the compound of theformula (I), the compound of the formula (VIIIa), the compound of theformula (VIIIa-1b), the compound of the formula (VIIIa-1c), the compoundof the formula (VIIIa-2a), the compound of the formula (VIIIa-2b), thecompound of the formula (VIIIa-2c), the compound of the formula(VIIIa-2d), the compound of the formula (VIIIa-2e), the compound of theformula (VIIIa-3a), or the compound of the formula (VIIIa-3b) having anaromatic ring substituted with chlorine, bromine or iodine, with asilylacetylene such as trimethylsilylacetylene by using palladiumacetate and triphenylphosphine at a temperature range of from −20 to150° C. for 0.5 to 120 hours, if necessary in the presence of a basesuch as triethylamine or pyridine, in a benzene solvent such as toluene,an ether solvent such as tetrahydrofuran or an amide solvent such asN,N-dimethylformamide, or a mixed solvent thereof.

[2454] The silyl group can be removed from the resulting silylacetylenecompound by treating the compound with a base such as potassiumcarbonate, potassium bicarbonate or sodium hydroxide in a solvent, forexample, an alcohol solvent such as methanol, an ether solvent such astetrahydrofuran, water, or a mixed solvent thereof.

[2455] [Preparation Example-25]

[2456] Conversion of a Halogen Atom into a Nitrile Group

[2457] When the compound of the formula (I), the compound of the formula(VIIIa), the compound of the formula (VIIIalb), the compound of theformula (VIIIa-1c), the compound of the formula (VIIIa-2a), the compoundof the formula (VIIIa-2b), the compound of the formula (VIIIa-2c), thecompound of the formula (VIIIa-2d), the compound of the formula(VIIIa-2e), the compound of the formula (VIIIa-3a), or the compound ofthe formula (VIIIa-3b) has an aromatic ring substituted with chlorine,bromine or iodine, such a halogen atom can be converted into a nitrilegroup by reacting with zinc cyanide in the presence of a transitionmetal catalyst. The conversion of chlorine, bromine or iodine into anitrile group can be carried out by reacting the compound of the formula(I), the compound of the formula (VIIIa), the compound of the formula(VIIIa-1b), the compound of the formula (VIIIa-1c), the compound of theformula (VIIIa-2a), the compound of the formula (VIIIa-2b), the compoundof the formula (VIIIa-2c), the compound of the formula (VIIIa-2d), thecompound of the formula (VIIIa-2e), the compound of the formula(VIIIa-3a), or the compound of the formula (VIIIa-3b) having an aromaticring substituted with chlorine, bromine or iodine, with zinc cyanide byusing a transition metal catalyst such astetrakis(triphenylphosphine)palladium (O) at a temperature range of from−20 to 150° C. for 0.5 to 120 hours, if necessary in the presence of abase such as triethylamine or pyridine, in a benzene solvent such astoluene, an ether solvent such as tetrahydrofuran or an amide solventsuch as N,N-dimethylformamide, or a mixed solvent thereof.

[2458] [Preparation process-26]

[2459] Conversion of a Halogen Atom into a Trifluoromethyl Group

[2460] When the compound of the formula (I), the compound of the formula(VIIIa), the compound of the formula (VIIIalb), the compound of theformula (VIIIa-1c), the compound of the formula (VIIIa-2a), the compoundof the formula (VIIIa-2b), the compound of the formula (VIIIa-2c), thecompound of the formula (VIIIa-2d), the compound of the formula(VIIIa-2e), the compound of the formula (VIIIa-3a), or the compound ofthe formula (VIIIa-3b) contains chlorine, bromine or iodine as asubstituent, such a halogen atom can be converted into a trifluoromethylgroup by reacting the compound with a trifluoromethylating reagent inthe presence of a metal catalyst. Described specifically, the conversionof chlorine, bromine or iodine into a trifluoromethyl group can beeffected by reacting the compound of the formula (I), the compound ofthe formula (VIIIa), the compound of the formula (VIIIa-1b), thecompound of the formula (VIIIa-1c), the compound of the formula(VIIIa-2a), the compound of the formula (VIIIa-2b), the compound of theformula (VIIIa-2c), the compound of the formula (VIIIa-2d), the compoundof the formula (VIIIa-2e), the compound of the formula (VIIIa-3a), orthe compound of the formula (VIIIa3b) containing chlorine, bromine oriodine as a substituent, with a trifluoromethylating reagent such asmethyl-2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of a metalcatalyst such as copper iodide at a temperature range of from 0 to 150°C. for 0.5 to 120 hours in a benzene solvent such as toluene, an ethersolvent such as tetrahydrofuran or an amide solvent such asN,N-dimethylformamide, or a mixed solvent thereof.

[2461] [Preparation Process-27]

[2462] Conversion of a Nitrile Group into a Tetrazole Group

[2463] When the compound of the formula (I) has a nitrile group as asubstituent, it can be converted into the compound of the formula (I)having a tetrazole group by reacting the former with sodium azide ortrimethylsilyl azide at 0 to 170° C. in the presence oftrimethylaluminum or di-nbutyltin oxide in a benzene solvent such asbenzene or toluene.

[2464] [Preparation Process-28]

[2465] Conversion of an Amidino Group into an AlkoxycarbonylamidinoGroup

[2466] When the compound of the formula (I) contains an amidino group,it can be converted into the compound of the formula (I) containing analkoxycarbonylamidino group by reacting the former with a reagent, forexample, an acid chloride such as alkyl chlorocarbonate or alkylpnitrobenzylcarbonate at −78 to 100° C. in the presence of a base in analkyl halide solvent such as dichloromethane or chloroform, an amidesolvent such as N,N-dimethylformamide or an ether solvent such astetrahydrofuran.

[2467] Examples of the base include sodium carbonate, potassiumcarbonate, pyridine, 2,6-lutidine, 4-dimethylaminopyridine,diazabicyclo[5.4.0]undec-7-en (DBU).

[2468] [Preparation Process-29]

[2469] The sulfonyl derivative of the formula (I) having a primary orsecondary amine on Q¹, Q², Q³, Q⁴ or T¹ or a substituent substitutabletherefor can be hydroxylated in a conventional manner.

[2470] For example, a sulfonyl derivative having a hydroxylated nitrogenatom can be obtained reacting the sulfonyl derivative of the formula (I)with a peroxide such as metachloroperbenzoic acid at −60 to 80° C.,preferably −20 to 40° C., for 0.5 to 120 hours in a benzene solvent suchas benzene, toluene or xylene, an ether solvent such as tetrahydrofuranor dimethoxyethane or an alkyl halide solvent such as dichlormethane,chloroform or carbon tetrachloride.

[2471] Alternatively, a sulfonyl derivative having a hydroxylatednitrogen atom can be obtained, for example, by reacting the sulfonylderivative of the formula (I) with a peroxide such as benzoyl peroxideat −60 to 80° C., preferably 20 to 40° C., for 0.5 to 120 hours in abenzene solvent such as benzene, toluene or xylene, an ether solventsuch as dimethoxyethane or an alkyl halide solvent such asdichlormethane, chloroform or carbon tetrachloride, thereby obtaining asulfonyl derivative having a benzoyloxylated nitrogen atom; and thensubjecting the resulting sulfonyl derivative having a benzoyloxylatednitrogen atom to hydrolysis in accordance with the process as describedin [Preparation Process-19].

[2472] The sulfonyl derivative of the formula (I) according to thepresent invention, salt thereof or solvate thereof has peculiar andexcellent FXa inhibitory activity and is therefore useful as acoagulation suppressor or a preventive and/or remedy for thrombosis orembolism.

[2473] Accordingly, the sulfonyl derivative of the present invention cantreat or prevent various diseases caused by thrombosis or embolism, forexample, cerebral infarction, cerebral embolism, myocardial infarction,pulmonary infarction, pulmonary embolism, Buerger's disease, deep veinthrombosis and disseminated intravascular coagulation syndrome, thrombusformation after valve replacement, reocclusion after revascularizationand formation of thrombus upon extracorporeal circulation, withoutacting on platelets.

[2474] The sulfonyl derivative of the present invention exhibits effectseven by the oral administration so that it can be administered eitherorally or parenterally. Upon administration, it can be formulated as apharmaceutical composition comprising the sulfonyl derivative and apharmaceutically acceptable carrier. The dose of the sulfonyl derivativecan be changed as needed depending on the symptom, age, weight and/orthe like of a patient. It is necessary to administer the derivative inan amount of 1 to 1000 mg/day, preferably 5 to 300 mg/day per adult.Although no particular limitation is imposed on the dosage form,examples include tablets, capsules, powders, granules, suspensions,syrups and dry syrups. The derivative together with ordinarily employedadditives such as excipient, lubricant or binder can be formulated intothe above-described dosage forms in accordance with the knownformulation technique.

[2475] No particular limitation is imposed on the dosage form in thecase of parenteral administration but examples include ointments,plasters, injections and suppositories. As an injection, the derivativemay be administered subcutaneously or intravenously or by intravenousdrip in an amount of 0.1 to 100 mg/day, preferably 0.5 to 30 mg/day peradult.

EXAMPLES

[2476] The present invention will hereinafter be described morespecifically by Referential Examples, Examples and Tests. It shouldhowever be borne in mind that the present invention is not limited to orby them.

[2477] Some of the starting material compounds used for preparing thesulfonyl derivative of the present invention are novel compounds. Thesecompounds and preparation process therefor will be described inReferential Examples.

[2478] Upon preparation of the compound, Merck Silica Gel 60 or YamazenSilica Gel for moderate pressure liquid chromatography were employed forsilica gel column chromatography.

[2479] In the nuclear magnetic resonance spectrum (NMR),tetramethylsilane was used an internal standard.

Referential Example 1 1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride and Trifluoroacetate

[2480] In dichloromethane (20 ml), tert-butyl 1-piperazine carboxylate(856 mg) was dissolved. To the resulting solution, triethylamine (0.77ml) and 6-chloro-2-naphthylsulfonyl chloride (WO96/10022)(1.20 g) wereadded, followed by stirring at room temperature for 5 hours. Thereaction mixture was concentrated under reduced pressure. Ethyl acetatewas added to the residue and the resulting mixture was washed with 1Nhydrochloric acid. The organic layer extracted was dried over anhydroussodium sulfate. The solvent was then distilled off under reducedpressure. The residue was dissolved in saturated hydrochloride inethanol (10 ml), followed by concentration under reduced pressure andwashing with ethyl acetate, whereby the hydrochloride (1.62 g, quant.)of the title compound was obtained as a colorless solid.

[2481]¹H-NMR (DMSO-d₆) δ: 3.1-3.4 (8H, m), 7.75 (1H, dd, J=8.8, 2.0 Hz),7.86 (1H, dd, J=8.8, 1.5 Hz), 8.22 (1H, d, J=8.8 Hz), 8.26-8.32 (2H, m),8.56 (1H, s), 8.63 (2H, br s).

[2482] MS (FAB) m/z: 311 [(M+H)⁺, Cl³⁵], 313 [(M+H)⁺, Cl³⁷].

[2483] Elementary analysis for C₁₄H₁₅ClN₂O₂S.HCl.0.1H₂O

[2484] Calculated: C, 48.17; H, 4.68, Cl, 20.31; N, 8.03; S, 9.19.

[2485] Found: C, 47.91; H, 4.68; Cl, 20.41; N, 7.80; S, 9.21.

[2486] Instead of the saturated solution hydrochloride in ethanol,treatment was carried out using trifluoroacetic acid, whereby thetrifluoroacetate was obtained.

[2487] Elementary analysis for C₁₄H₁₅ClN₂O₂S.CF₃CO₂H

[2488] Calculated: C, 45.24; H, 3.80, Cl, 8.35; F, 13.42; N, 6.59; S,7.55.

[2489] Found: C, 44.84; H, 3.80; Cl, 8.27; F, 13.72; N, 6.29; S, 7.50.

Referential Example 2 4-(4-Pridyl)benzoic Acid Hydrochloride

[2490] At room temperature, 4-bromopyridine hydrochloride (11.7 g) and4-carboxyphenylboronic acid (10.0 g) were dissolved in toluene (250 ml)and water (250 ml). To the resulting solution,tetrakis(triphenylphosphine)palladium (0) (5.00 g) and anhydrous sodiumcarbonate (25.4 g) were added successively, followed by refluxing underheat at 120° C. for 19 hours. After allowed to cool down to roomtemperature, the reaction mixture was added with ethyl acetate andwater, whereby the water layer was separated. The organic layer wasextracted twice with water. All the water layers so obtained werecombined and to the resulting solution, concentrated hydrochloric acidwas added to make it acidic, followed by washing with ethyl acetateagain. The solvent was distilled off from the water layer until itdecreased to 100 ml. The colorless solid so precipitated was collectedby filtration and dried under reduced pressure, whereby the titlecompound (8.37 g, 59%) was obtained.

[2491]¹H-NMR (DMSO-d₆) δ: 8.11 (2H, d, J=8.8 Hz), 8.14 (2H, d, J=8.8Hz), 8.35 (2H, d, J=6.6 Hz), 8.97 (2H, d, J=6.6 Hz).

[2492] Eemerentary analysis for C₁₂H₉NO₂.HCl.0.3H₂O

[2493] Calculated: C, 59.79; H, 4.43, N, 5.81

[2494] Found: C, 59.87; H, 4.35; N, 5.53.

[2495] MS (FAB) m/z: 200 (M+H)⁺.

Referential Example 31-tert-Butoxycarbonyl-4-[4-(4-pyridyl)benzoyl]piperazine

[2496] In N,N-dimethylformamide (40 ml), 4-(4-pyridyl)benzoic acidhydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg)were suspended. To the resulting suspension, 1-hydroxybenzotriazole (374mg) and N-methylmorpholine (336 μl) were added. The resulting mixturewas ice cooled, followed by the addition of1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg).After stirring at room temperature for 7 hours, the solvent wasdistilled off. The residue was purified by chromatography on a silicagel column (2% methanol—dichloromethane), followed by washing withhexane, whereby the title compound (905 mg, 89%) was obtained.

[2497]¹H-NMR (CDCl₃)δ: 1.48 (9H, s), 3.40-3.91 (8H, m), 7.51 (2H, d,J=5.9 Hz), 7.53 (2H, d, J=8.1 Hz), 7.69 (2H, d, J=8.1 Hz), 8.69 (2H, d,J=5.9 Hz).

[2498] Elementary analysis for C₂₁H₂₅N₃O₃

[2499] Calculated: C, 68.64; H, 6.86, N, 11.44.

[2500] Found: C, 68.48; H, 6.84; N, 11.17.

Referential Example 4 1-[4-(4-Pyridyl)benzoyl]piperazineditrifluoroacetate

[2501] In dichloromethane (30 ml),1-tert-butoxycarbonyl-4-[4-(4-pyridyl)benzoyl]piperazine (944 mg) wasdissolved. Under ice cooling, trifluoroacetic acid (30 ml) was added tothe resulting solution, followed by stirring at room temperature for onehour. The solvent was distilled off. Tetrahydrofuran was added to theresidue to solidify the same, whereby the title compound (1.28 g, 100%)was obtained as a colorless amorphous solid.

[2502]¹H-NMR (DMSO-d₆) δ: 3.1-3.3 (4H, br s), 3.5-4.0 (4H, m), 7.65 (2H,d, J=7.8 Hz), 7.95-8.05 (4H, m), 8.79 (2H, d, J=5.4 Hz), 8.95-9.10 (1H,br s)

Referential Example 54-tert-Butoxycarbonyl-2-ethoxycarbonyl-1-[4-(4-pyridyl)benzoyl]piperazine

[2503] In toluene (150 ml), 1,2-dibromopropionic acid (58.0 g) wasdissolved. To the resulting solution, a solution ofN,N′-dibenzylethylenediamine (53.5 g) and triethylamine (53 ml) intoluene (toluene: 50 ml) was added dropwise under ice cooling. Toluene(100 ml) was added again to the reaction mixture, followed by stirringat room temperature for 14 hours, addition of toluene (100 ml) again andstirring at 60 to 80° C. for 4 hours. The insoluble matter was filteredoff. The filtrate was washed with water and dried over anhydrouspotassium carbonate. The solvent was then distilled off under reducedpressure. The residue was dissolved in acetic acid (200 ml). To theresulting solution, 10% palladium carbon (water content: about 50%, 40g) was added, followed by catalytic reduction under 4 atmosphericpressure for 4 hours. The catalyst was filtered off and the filtrate wasdistilled off under reduced pressure. To the residue, dichloromethaneand a saturated aqueous solution of potassium carbonate were added toseparate the organic layer, followed by drying over anhydrous potassiumcarbonate. The solvent was distilled off under reduced pressure. Theresidue was dissolved in dichloromethane (350 ml), followed by theaddition of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (46.5g) under ice cooling. The reaction mixture was heated gradually to roomtemperature, at which stirring was conducted for 14 hours. The solventwas distilled off under reduced pressure. The residue was purified bychromatography on a silica gel column (dichloromethane˜2%methanol—dichloromethane), whereby1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (5.82 g, 10%) wasobtained.

[2504] In the same manner as in Referential Example 3, the a reactionwas conducted using the resulting product and 4-(4-pyridyl)benzoic acidhydrochloride as starting materials, whereby the title compound wasobtained.

[2505]¹H-NMR (CDCl₃)δ: 1.2-1.4 (3H, m), 1.46 (9H, s), 2.7-5.4 (7H, m),7.51 (2H, d, J=5.2 Hz), 7.59 (2H, d, J=7.6 Hz), 7.69 (2H, d, J=7.6 Hz),8.69 (2H, d, J=5.2 Hz).

[2506] MS (FAB) m/z: 440 (M+H)⁺.

Referential Example 6 6-(4-Pyridyl)nicotinic Acid Hydrochloride

[2507] In tetrahydrofuran (20 ml), 6-chloronicotinic acid (535 mg) anddiethyl (4-pyridyl)borane (Chem. Pharm. Bull., 33, 4755, 1985) (500 mg)were dissolved. To the resulting solution, tetrabutylammonium bromide(546 mg), potassium hydrochloride (570 mg), tetrakis(triphenylphosphine)palladium (O) (392 mg) and water (0.5 ml) were added under an argonatmosphere, followed by heating under reflux for 6 hours. Dilutehydrochloric acid was added to the reaction mixture to make it acidic.Water and ethyl acetate were poured into the resulting mixture forextraction. The water layer so extracted was distilled off under reducedpressure. The residue was purified by chromatography through a syntheticadsorbent (“Diaion® HP-20”, water˜50% acetonitrile—water). To theresulting fraction, dilute hydrochloric acid was added to make itacidic. The solvent was then distilled off. Tetrahydrofuran was added tothe residue and the precipitate was collected by filtration, whereby thetitle compound (269 mg, 32%) was obtained.

[2508]¹H-NMR (DMSO-d₆) δ: 8.45-8.55 (2H, m), 8.65 (2H, d, J=6.8 Hz),9.03 (2H, d, J=6.8 Hz), 9.27 (1H, s).

[2509] MS (FAB) m/z: 201 (M+H)+

Referential Example 7 Methyl 4-(3-pyridyl)benzoate

[2510] In tetrahydrofuran (100 ml), methyl 4-bromobenzoate (5.04 g) anddiethyl-3-pyridylborane (Chem. Pharm. Bull., 33, 4755, 1985) (2.30 g)were dissolved, followed by the addition of tetrabutylammonium bromide(2.51 g), potassium hydroxide (2.63 g),tetrakis(triphenylphosphine)palladium (O) (1.8 g) and water (1 ml) underan argon atmosphere. The resulting mixture was heated under reflux for 2hours. After ice cooling, an aqueous ammonium chloride solution andethyl acetate were added to the reaction mixture. The organic layer soseparated was dried over anhydrous magnesium sulfate. The residueobtained by distilling off the solvent was purified by chromatography ona silica gel column (hexane:ethyl acetate=1:1). The solvent was thendistilled off. To the residue, methanol and 1N aqueous hydrochloric acidin ethanol were added. The solvent was distilled off again.Tetrahydrofuran was added to the residue and the solid so precipitatedwas collected by filtration. After drying, the title compound (1.76 g,45%) was obtained as a colorless solid.

[2511]¹H-NMR (DMSO-d₆) δ: 3.91 (3H, s), 8.0-8.1 (3H, m), 8.18.15 (2H,m), 8.75-8.85 (1H, m), 8.85-8.95 (1H, m), 9.25-9.3 (1H, m).

Referential Example 8 4-(3-Pyridyl)benzoic Acid Hydrochloride

[2512] At room temperature, methyl 4-(3-pyridyl)benzoate (1.76 g) wasdissolved in a mixed solvent of 1N hydrochloric acid (50 ml) and dioxane(50 ml), followed by heating under reflux for 4 hours. The solvent wasthen distilled off under reduced pressure. Tetrahydrofuran was added tothe residue, followed by washing, whereby the title compound (1.55 g,93%) was obtained as a colorless solid.

[2513]¹H-NMR (DMSO-d₆) δ: 7.95-8.0 (3H, m), 8.10 (2H, d, J=8.3 Hz),8.65-8.75 (1H, m), 8.8-8.9 (1H, m), 9.22 (1H, d, J=2.0 Hz)

Referential Example 9 Methyl 4-(2-aminopyridin-5-yl)benzoate

[2514] In the same manner as in Example 2, a reaction was conductedusing 5-bromo-2-aminopyridine and 4-carboxyphenyboronic acid as startingmaterials, whereby 4(2-aminopyridin-5-yl)benzoic acid was obtained.

[2515] The resulting 4-(2-aminopyridin-5-yl)benzoic acid (684 mg) wasdissolved in methanol (50 ml) at room temperature, followed by theaddition of concentrated sulfuric acid (1 ml). After heating underreflux for 2 hours, the reaction mixture was made weakly alkaline withan aqueous solution of sodium bicarbonate. Water and ethyl acetate wereadded to the resulting mixture to separate the organic layer. Theorganic layer was then dried over anhydrous magnesium sulfate. Thesolvent was distilled off. Hexane was added to the residue forcrystallization, whereby the title compound (243 mg, 23%) was obtained.

[2516]¹H-NMR (CDCl₃) δ: 3.94 (3H, s) 4.57 (2H, br s), 6.60 (1H, d, J=8.8Hz), 7.58 (2H, d, J=8.8 Hz), 7.72 (1H, dd, J=8.8, 2.4 Hz), 8.09 (2H, d,J=8.8 Hz), 8.38 (1H, d, J=2.4 Hz).

[2517] MS (FAB) m/z: 229 (M+H)⁺.

[2518] Elementary analysis for C₁₃H₁₂N₂O₂

[2519] Calculated: C, 68.41; H, 5.30, N, 12.27.

[2520] Found: C, 68.78; H, 5.45; N, 12.09.

Referential Example 10 Methyl4-[2-(tert-Butoxycarbonylamino)pyridin-5-yl]benzoate

[2521] At room temperature, methyl 4-(2-aminopyridin-5-yl)benzoate (200mg) was-suspended in tert-butanol (20 ml). To the resulting suspension,di-tert-butyl dicarbonate (286 mg) was added and the resulting mixturewas stirred for 24 hours. After the solvent was distilled off, theresidue was purified by chromatography on a silica gel column (1%methanol—dichloromethane), whereby the title compound (155 mg, 54%) wasobtained as a colorless solid.

[2522]¹H-NMR (CDCl₃) δ: 1.55 (9H, s), 3.95 (3H, s), 7.63 (2H, d, J=8.3Hz), 7.92 (1H, dd, J=8.8, 2.4 Hz), 8.07 (1H, d, J=8.8 Hz), 8.09 (1H, brs), 8.12 (2H, d, J=8.3 Hz), 8.55 (1H, d, J=2.4 Hz).

[2523] MS (FAB) m/z: 329 (M+H)⁺.

[2524] Elementary analysis for C₁₈H₂₀N₂O₄

[2525] Calculated: C, 65.84; H, 6.14, N, 8.53;

[2526] Found: C, 65.67; H, 6.02; N, 8.40.

Referential Example 114-[2-(tert-Butoxycarbonylamino)pyridin-5-yl]benzoic Acid

[2527] At room temperature, methyl4-[2-(tert-butoxycarbonylamino)pyridin-5-yl]benzoate (250 mg) wassuspended in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10ml), followed by the addition of a 1N aqueous sodium hydroxide solution(8 ml). The resulting mixture was stirred for 5 hours. The reactionmixture was made weakly acidic with an aqueous citric acid solution,followed by the addition of saturated saline and n-butanol to separatethe organic layer. The organic layer was then dried over anhydrousmagnesium sulfate. The solvent was distilled off, whereby the titlecompound (120 mg, 49%) was obtained as a crude purified product.

[2528]¹H-NMR (DMSO-d₆) δ: 1.49 (9H, s), 7.83 (2H, d, J=8.3 Hz), 7.91(1H, d, J=8.8 Hz), 8.02 (2H, d, J=8.3 Hz), 8.13 (1H, dd, J=8.8, 2.4 Hz),8.65 (1H, d, J=2.4 Hz), 9.95 (1H, s), 12.99 (1H, br s).

Referential Example 121-[4-[2-(tert-Butoxycarbonylamino)pyridin-5-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2529] In a mixed solvent of dichloromethane (20 ml) andN,N-dimethylformamide (1 ml),4-[2-(tert-butoxycarbonyl)amino]pyridin-5-yl]benzoic acid (74 mg) and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (110mg) were suspended. To the resulting suspension, 1-hydroxybenzotriazole(35 mg) and N-methylmorpholine (34 μl) were added, followed by theaddition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(68 mg) under ice cooling. After stirring at room temperature for 6hours, the solvent was distilled off. The residue was purified bychromatography on a silica gel column (1% methanol—dichloromethane). Thesolvent was then distilled off, whereby the title compound (128 mg, 90%)was obtained.

[2530]¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 3.00-3,30 (4H, m), 3.50-4.10 (4H,m), 7.39 (2H, d, J=7.8 Hz), 7.54 (2H, d, J=7.8 Hz), 7.60 (1H, dd, J=8.8,2.0 Hz), 7.71 (1H, dd, J=8.8, 1.5 Hz), 7.84 (1H, dd, J=8.8, 2.4 Hz),7.88 (1H, br s), 7.9-8.0 (3H, m), 8.03 (1H, d, J=8.8 Hz), 8.31 (1H, s),8.46 (1H, d, J=2.4 Hz).

Referential Example 13 4-(4-Aminophenyl)benzoic Acid Hydrochloride

[2531] In the same manner as in Referential Example 2, a reaction wasconducted using 4-bromoaniline and 4-carboxyphenylboronic acid asstarting materials, whereby the title compound was obtained.

[2532]¹H-NMR (DMSO-d₆) δ: 7.31 (2H, d, J=7.3 Hz), 7.75-7.85 (4H, m),8.09 (2H, d, J=8.3 Hz).

[2533] MS (FAB) m/z: 228 (M+H)⁺.

[2534] Elementary analysis for C₁₃H₁₁NO₂.HCl

[2535] Calculated: C, 62.53; H, 4.84, N, 5.61; Cl, 14.20.

[2536] Found: C, 62.33; H, 4.83; N, 5.50; Cl, 14.14.

Referential Example 14 Methyl4-[4-(tert-butoxycarbonylamino)phenyl]benzoate

[2537] In the same manner as in Referential Example 9 or 10, a reactionwas conducted using 4-(4-aminophenyl)benzoic acid hydrochloride as astarting material, whereby the title compound was obtained.

[2538]¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 3.94 (3H, s), 6.56 (1H, br s),7.46 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.3 Hz),8.08 (2H, d, J=8.3 Hz).

[2539] MS (FAB) m/z: 328 (M+H)⁺.

[2540] Elementary analysis for C₁₉H₂₁NO₄

[2541] Calculated: C, 69.71; H, 6.47, N, 4.28.

[2542] Found: C, 69.49; H, 6.44; N, 4.42.

Referential Example 15 4-[4-(tert-Butoxycarbonylamino)phenyl]benzoicAcid

[2543] In the same manner as in Referential Example 11, a reaction wasconducted using methyl 4-[4-(tert-butoxycarbonylamino)phenylbenzoate(501 mg), whereby the title compound (426 mg, 89%) was obtained.

[2544]¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 6.57 (1H, br s), 7.47 (2H, d,J=8.3 Hz), 7.59 (2H, d, J=8.3 Hz), 7.66 (2H, d, J=8.3 Hz), 8.13 (2H, d,J=8.3 Hz).

[2545] MS (FAB) m/z: 314 (M+H)⁺.

[2546] Elementary analysis for C₁₈H₁₉NO₄

[2547] Calculated: C, 68.99; H, 6.11, N, 4.47.

[2548] Found: C, 68.91; H, 6.27; N, 4.24.

Referential Example 161-(4-[4-(tert-Butoxycarbonylamino)phenyl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2549] In the same manner as in Referential Example 12, a reaction wasconducted using 4-[4-(tert-butoxycarbonylamino)phenylbenzoic acid (150mg) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate(203 mg) as starting materials, whereby the title compound (303 mg,100%) was obtained.

[2550]¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 2.90-3.30 (4H, m), 3.50-4.10 (4H,m), 6.56 (1H, s), 7.35 (2H, d, J=8.3 Hz), 7.44 (2H, d, J=8.3 Hz), 7.49(2H, d, J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz), 7.59 (1H, dd, J=8.8, 2.0 Hz),7.76 (1H, dd, J=8.8, 2.0 Hz), 7.90-7.95 (3H, m), 8.30 (1H, br s).

Referential Example 17 Methyl 4-acetylbenzoate

[2551] In a mixed solvent of tetrahydrofuran (100 ml) and methanol (7ml), methyl 4-acetylbenzoate (3.28 g) was dissolved at room temperature,followed by the addition of trimethylsilyldiazomethane (a 2.0M hexanesolution, 12 ml) in portions under ice cooling. After heating to roomtemperature and stirring for 30 minutes, the solvent was distilled off.To the residue, an aqueous solution of sodium bicarbonate and ether wereadded. The organic layer so separated was dried over anhydrous magnesiumsulfate. After the solvent was distilled off, the residue wascrystallized from hexane, whereby the title compound (2.90 g, 82%) wasobtained. ¹H-NMR (CDCl₃) δ: 2.65 (3H, s), 3.96 (3H, s), 8.01 (2H, d,J=8.3 Hz), 8.13 (2H, d, J=8.3 Hz).

[2552] MS (EI) m/z: 178M⁺.

[2553] Elementary analysis for C₁₀H₁₀O₃

[2554] Calculated: C, 67.41; H, 5.66.

[2555] Found: C, 67.28; H. 5-0.53.

Referential Example 18 Methyl 4-bromoacetylbenzoate

[2556] At 15° C., methyl 4-acetylbenzoate (2.23 g) was dissolved in ahydrobromic acid acetic acid solution (30%, 10 ml). Bromine wasgradually added dropwise to the reaction mixture to maintain itstemperature at 15° C. After stirring for 10 minutes, the reactionmixture was cooled to 4° C. A mixed solvent of methanol (50 ml) andwater (50 ml) was added to the reaction mixture for crystallization,followed by washing with hexane. By the collection through filtration,the title compound (2.29 g, 71%) was obtained as a colorless solid.

[2557]¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 4.47 (2H, s), 8.05 (2H, d, J=8.8Hz), 8.16 (2H, d, J=8.8 Hz).

[2558] MS (FAB) m/z 257 [(M+H)⁺, ⁷⁹Br], 259 [(M+H)⁺, ⁸¹Br].

[2559] Elementary analysis for C₁₀H₉BrO₃

[2560] Calculated: C, 46.72; H, 3.53.

[2561] Found: C, 46.36; H, 3.63.

Referential Example 19 Methyl 4-(2-aminothiazol-4-yl)benzoate

[2562] At room temperature, methyl 4-bromoacetylbenzoate (1.00 g) andthiourea (296 mg) were dissolved in isopropanol (100 ml), followed byheating under reflux for 15 minutes. Under stirring at the sametemperature, anhydrous sodium carbonate (206 mg) was added to thereaction mixture. The resulting mixture was heated under reflux for 20minutes. After completion of the reaction, water (50 ml) was added underice cooling and the solid so precipitated was collected by filtration.The solid was dissolved in water and dichloromethane. The organic layerso separated was dried over anhydrous sodium sulfate. The solvent wasthen distilled off. The pale yellow solid so precipitated was washedwith ether, whereby the title compound (634 mg, 70%) was obtained.

[2563]¹H-NMR (CDCl₃) δ: 3.93 (3H, s), 4.96 (2H, br s), 6.88 (1H, s),7.85 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=8.8 Hz).

[2564] MS (FAB) m/z: 235 (M+H)⁺.

Referential Example 20 4-(2-Aminothiazol-4-yl)benzoic Acid

[2565] At room temperature, methyl 4-(2-aminothiazol-4-yl)benzoate (300mg) was suspended in a mixed solvent of tetrahydrofuran (5 ml) andmethanol (5 ml), followed by the addition of a 1N aqueous sodiumhydroxide solution (10 ml). The resulting mixture was stirred for onehour. To the reaction mixture, N,N-dimethylformamide (5 ml) was added,followed by heating under reflux for 6 hours. After completion of thereaction, the solvent was distilled off. To the residue, water and 1Nhydrochloric acid were added successively and the pale yellow solid soprecipitated was collected by filtration, whereby the title compound(229 mg, 69%) was obtained as a pale yellow solid.

[2566]¹H-NMR (DMSO-d₆) δ: 7.30 (1H, br s), 7.87 (2H, d, J=8.3 Hz),7.95-8.00 (2H, m)

[2567] MS (FAB) m/z: 221 (M+H)⁺.

[2568] Elementary analysis for C₁₀H₈N₂O₂S.0.75HCl.0.6H₂O

[2569] Calculated: C, 46.48; H, 3.88, N, 10.84; Cl, 10.29; S, 12.41.

[2570] Found: C, 46.36; H, 4.12, N, 10.64; Cl, 10.05; S, 12.33.

Referential Example 21 Methyl 4-(imidazol-4-yl)benzoate

[2571] At room temperature, methyl 4-bromoacetylbenzoate (2 g) wasdissolved in formamide (100 ml), followed by stirring at 180° C. for 90minutes. After completion of the reaction, the reaction mixture was icecooled and dissolved in water and 1N hydrochloric acid. The resultingsolution was purified by chromatography through a synthetic adsorbent(“Diaion HP-20”, water˜50% acetonitrile—water). The crude product soobtained was purified further by chromatography on a silica gel column(5% methanol—dichloromethane), whereby the title compound (844 mg, 54%)was obtained as a pale yellow solid.

[2572]¹H-NMR (CDCl₃) δ: 3.93 (3H, s), 7.46 (1H, s), 7.75 (1H, s), 7.86(2H, m), 8.07 (2H, d, J=8.3 Hz).

[2573] MS (FAB) m/z: 203 (M+H)⁺.

Referential Example 22 Methyl4-[1-triphenylmethylimidazol-4(5)-yl]benzoate

[2574] Methyl 4-(imidazol-4-yl)benzoate (828 mg) was dissolved indichloromethane (50 ml), followed by the addition ofdiisopropylethylamine (856 μl) and triphenylmethyl chloride (1.37 g)under ice cooling. The resulting mixture was stirred at room temperaturefor 16 hours. The solvent was distilled off. The residue was purified bychromatography on a silica gel column (dichloromethane), whereby thetitle compound (1.08 g, 59%) was obtained as a colorless glassy solid.

[2575]¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 7.15-7.22 (6H, m), 7.23 (1H, d,J=1.5 Hz), 7.30-7.40 (15H, m), 7.52 (1H, d, J=1.5 Hz), 7.79 (2H, d,J=8.3 Hz), 8.01 (2H, d, J=8.3 Hz).

[2576] MS (FAB) m/z: 445 (M+H)⁺.

Referential Example 23 4-[1-Triphenylmethylimidazol-4(5)-yl]benzoic Acid

[2577] At room temperature, methyl4-[1-triphenylmethylimidazol-4(5)-yl]benzoate (1.04 g) was dissolved ina mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml). To theresulting solution, a 3N aqueous sodium hydroxide solution (6 ml) wasadded, followed by stirring for 5 hours. Tetrahydrofuran and methanolwere removed by distillation under reduced pressure. An aqueous citricacid solution was added to the residue to make it weakly acidic,followed by the addition of water and dichloromethane. The organic layerso separated was washed with a saturated aqueous NaCl solution and driedover anhydrous sodium sulfate. The solvent was distilled off, wherebythe title compound (1.13 g, quant.) was obtained as a crude purifiedproduct in the form of a colorless glassy solid.

[2578]¹H-NMR (CDCl₃) δ: 7.15-7.22 (6H, m), 7.23 (1H, d, J=1.5 Hz),7.30-7.40 (9H, m), 7.69 (1H, d, J=1.5 Hz), 7.81 (2H, d, J=8.3 Hz), 8.10(2H, d, J=8.3 Hz).

Referential Example 241-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-[1-triphenylmethylimidazol-4(5)-yl]benzoyl]piperazine

[2579] In the same manner as in Referential Example 12, a reaction wasconducted by using 4-[1-triphenylmethylimidazol-4(5)-yl]benzoic acid(371 mg) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride (300 mg) as starting materials, whereby the title compound(560 mg, 90%) was obtained in the form of a colorless glassy solid.

[2580]¹H-NMR (CDCl₃) δ: 2.90-3.30 (4H, m), 3.50-4.10 (4H, m), 7.15-7.20(6H, m), 7.28 (2H, d, J=8.3 Hz), 7.30-7.40 (9H, m), 7.49 (1H, d, J=1.0Hz), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.71 (2H, d, J=8.3 Hz), 7.75 (1H, dd,J=8.8, 1.5 Hz), 7.90-7.95 (3H, m), 8.29 (1H, br s).

[2581] MS (FAB) m/z: 723 (M+H)⁺.

Referential Example 25 4-[2-Aminoimidazol-4-yl]benzoic AcidHydrochloride

[2582] At room temperature, methyl 4-bromoacetylbenzoate (1.37 g) andacetylguanidine (1.62 g) were suspended in acetonitrile, followed byheating under reflux for 16 hours. The solvent was then distilled offunder reduced pressure. Water was added to the residue. The insolublematter so precipitated was collected by filtration, followed by washingwith ethanol, whereby methyl 4-[2aminoimidazol-4-yl]benzoate wasobtained. The resulting product was dissolved in a mixed solvent ofdioxane (10 ml) and 1N hydrochloric acid (10 ml), followed by heatingunder reflux for 8 hours. The residue obtained by distilling off thesolvent was solidified by tetrahydrofuran and then collected byfiltration, whereby the title compound (500 mg, 39%) was obtained.

[2583]¹H-NMR (DMSO-d₆) δ: 7.55-7.65 (3H, m), 7.80 (2H, d, J=8.3 Hz),7.98 (2H, d, J=8.3 Hz), 12.2-13.3 (3H, m).

[2584] MS (FAB) m/z: 204 (M+H)⁺.

[2585] Elementary analysis for C₁₀H₉N₃O₂.HCl.0.5H₂O

[2586] Calculated: C, 48.30; H, 4.46; N, 16.90; Cl, 14.26.

[2587] Found: C, 48.03; H, 4.10; N, 16.49; Cl, 14.12.

Referential Example 261-[4-Bromo-2-(tert-butoxycarbonyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2588] In dichloromethane (200 ml), 4-bromophthalic anhydride (1.96 g)and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (3.00g) were suspended under ice cooling. To the resulting suspension,diisopropylethylamine (3.76 ml) was added, followed by stirring for 20minutes. To the reaction mixture, dilute hydrochloric acid anddichloromethane were added. The organic layer so separated was driedover anhydrous sodium sulfate. The solvent was concentrated so that thevolume was reduced to 200 ml. To the concentrate,N,N′-diisopropyl-O-tert-butylisourea (2.6 g) was added under ice coolingand the resulting mixture was stirred at room temperature for 3 days.Dilute hydrochloric acid and dichloromethane were added to the reactionmixture. The organic layer so separated was dried over anhydrous sodiumsulfate. The residue was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=3:11:1), whereby the title compound (1.78g, 35%) was obtained as a colorless solid.

[2589]¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 2.90-3.40 (6H, m), 3.80-4.00 (2H,m), 7.01 (1H, d, J=8.3 Hz), 7.59 (1H, dd, J=8.3, 2.0 Hz), 7.61 (1H, dd,J=8.3, 2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.85-7.95 (3H, m), 8.00(1H, d, J=2.0 Hz), 8.29 (1H, br s).

Referential Example 271-[2-tert-Butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[2590] In the same manner as in Referential Example 7, a reaction wasconducted using1-[4-bromo-2-(tert-butoxycarbonyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineand diethyl(4-pyridyl)borane as starting materials, whereby the titlecompound was obtained.

[2591]¹H-NMR (CDCl₃) δ: 1.37 (9H, s), 2.80-3.50 (6H, m), 3.80-4.00 (2H,m), 7.40 (1H, d, J=7.8 Hz), 7.60 (1H, dd, J=8.8, 2.0 Hz), 7.77 (1H, dd,J=8.3, 1.5 Hz), 7.87 (1H, dd, J=7.8, 2.0 Hz), 7.90-7.95 (3H, m), 8.10(2H, d, J=6.8 Hz), 8.25 (1H, d, J=2.0 Hz), 8.31 (1H, br s), 8.90 (2H, d,J=6.8 Hz).

[2592] MS (FAB) m/z: 592 (M+H)⁺.

[2593] Elementary analysis for C₃₁H₃₀ClN₃O₅S.HCl.0.2H₂O.THF

[2594] Calculated: C, 59.69; H, 5.64; N, 5.97; Cl, 10.07; S, 4.55.

[2595] Found: C, 59.55; H, 5.45; N, 5.87; Cl, 9.97; S, 4.68.

Referential Example 28 5-(4-Pyridyl)thiophene-2carboxylic AcidHydrochloride

[2596] In the same manner as in Referential Example 6, a reaction wasconducted using 5-bromothiophene-2-carboxylic acid and diethyl(4-pyridyl)borane as starting materials, whereby the title compound wasobtained.

[2597]¹H-NMR (DMSO-d₆) δ: 7.87 (1H, d, J=3.9 Hz), 8.17 (1H, d, J=3.9Hz), 8.29 (2H, d, J=6.8 Hz), 8.88 (2H, d, J=6.8 Hz).

[2598] MS (FAB) m/z: 206 (M+H)⁺.

[2599] Elementary analysis for C₁₀H₇NO₂S.HCl.0.8H₂O

[2600] Calculated: C, 46.90; H, 3-0.78; N, 5.47; Cl, 13.84; S, 12.52.

[2601] Found: C, 46.77; H, 3.76; N, 5.27; Cl, 13.83; S, 2.56.

Referential Example 29 5-(4-Pyridyl)furan-2-carboxylic AcidHydrochloride

[2602] In the same manner as in Referential Example 6, a reaction wasconducted using 5-bromofuran-2-carboxylic acid and diethyl(4-pyridyl)borane as starting materials, whereby the title compound wasobtained.

[2603]¹H-NMR (DMSO-d₆) δ: 7.49 (1H, d, J=3.4 Hz), 7.80-7.90 (1H, m),8.20-8.30 (2H, m), 8.85-8.95 (2H, m).

Referential Example 30 4-(2-Pyridyl)benzoic Acid Hydrochloride

[2604] To water (200 ml), 2-(p-tolyl)pyridine (17.2 g) was added. To theresulting mixture, potassium permanganate (21.0 g) was added, followedby heating under reflux for 18 hours. After the precipitate was filteredoff, dichloromethane was added to the filtrate to separate the waterlayer. The water layer was then made acidic with 2N hydrochloric acid.The acidic aqueous solution was concentrated. The precipitate wascollected by filtration, followed by washing with water and ethylacetate, whereby the title compound (7.07 g, 35%) was obtained as awhite solid.

[2605]¹H-NMR (DMSO-d₆) δ: 7.60 (1H, t, J=5.9 Hz), 8.08 (2H, d, J=7.8Hz), 8.17 (2H, m), 8.21 (2H, d, J=7.8 Hz), 8.78 (1H, d, J=4.9 Hz).

[2606] MS (EI) m/z: 199M+.

Referential Example 31 1-[(E)-4-Chlorostyrylsulfonyl)piperazineHydrochloride

[2607] In the same manner as in Referential Example 1, a reaction wasconducted using tert-butyl 1-piperazinecarboxylate and(E)-4-chlorostyrylsulfonyl chloride as starting materials, whereby thetitle compound was obtained.

[2608]¹H-NMR (DMSO-d₆) δ: 3.20 (4H, br s), 3.33-3.38 (4H, m), 7.47 (2H,s), 7.53 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=8.8 Hz).

[2609] Elementary analysis for C₁₂H₁₅ClN₂O₂S.HCl

[2610] Calculated: C, 44.59; H, 4.99, Cl, 21.94; N, 8.67; S, 9.92.

[2611] Found: C, 44.42; H, 4.78, Cl, 21.83; N, 8.68; S, 9.87.

Referential Example 32 4-(2,4-Diamino-6-pyrimidyl)benzoic AcidHydrochloride

[2612] In toluene (9 ml), 6-chloro-2,4-diaminopyrimidine (434 mg) wasdissolved, followed by the addition of 4-carboxyphenylboronic acid (667mg), ethanol (2.5 ml), sodium carbonate (635 mg), water (3.0 ml) andbis(triphenylphosphine)palladium (II) dichloride (65 mg). The resultingmixture was heated under reflux for 24 hours under an argon gasatmosphere. Ethyl acetate and water were added to the reaction mixture.The water layer so separated was made acidic with 2N hydrochloric acid.The insoluble matter was collected by filtration, washed with water andtetrahydrofuran and then dried, whereby the title compound (371 mg, 54%)was obtained.

[2613]¹H-NMR (DMSO-d₆) δ: 6.43 (1H, s), 7.30-7.80 (2H, br), 7.96 (2H, d,J=7.8 Hz), 8.12 (2H, d, J=7.8 Hz), 8.27 (2H, br s), 12.77 (1H, br),13.33 (1H, br).

[2614] MS (EI) m/z: 230M+.

[2615] Elementary analysis for C₁₁H₁₀N₄O₂S.0.95HCl.1.9H₂O

[2616] Calculated: C, 44.17; H, 4.97; Cl, 11.26; N, 18.73.

[2617] Found: C, 44.33; H, 4.97; Cl, 11.32; N, 18.65.

Referential Example 331-tert-Butoxycarbonyl-4-[4-(2-pyridyl)benzoyl]piperazine

[2618] In the same manner as in Referential Example 3, a reaction wasconducted using 4-(2-pyridyl)benzoic acid hydrochloride obtained inReferential Example 30 and tert-butyl-1-piperazinecarboxylate asstarting materials, whereby the title compound was obtained.

[2619]¹H-NMR (CDCl₃)δ: 1.47 (9H, s), 3.43 (4H, br), 3.51 (2H, br), 3.76(2H, br), 7.28 (1H, d, J=5.9 Hz), 7.52 (2H, d, J=7.8 Hz), 7.76 (1H, m),7.79 (1H, m), 8.05 (2H, d, J=7.8 Hz), 8.71 (1H, d, J=4.9).

[2620] MS (FAB) m/z: 368 (M+H)⁺.

[2621] Elementary analysis for C₂₁H₂₅N₃O₃.0.1H₂O

[2622] Calculated: C, 68.31; H, 6.88; N, 11.38;

[2623] Found: C, 68.26; H, 6.86; N, 11.42.

Referential Example 342-[4-[[4-(tert-Butoxycarbonyl)piperazin-1-yl)carbonyl)phenyl]pyridineN-oxide

[2624] At −10° C., metachloroperbenzoic acid (789 mg) was added to asolution of 1-tert-butoxycarbonyl-4-[4-(2-pyridyl)benzoyl]piperazine(517 mg) in dichloromethane (dichloromethane: 8 ml). The resultingmixture was stirred for 24 hours, followed by dilution withdichloromethane. A small amount of an aqueous sodium thiosulfatesolution and a saturated aqueous NaCl solution were added to the dilutesolution. The organic layer so separated was washed with a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous NaClsolution and then dried over anhydrous sodium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (dichloromethanemethanol=20:1), whereby the title compound (415 mg, 77%) was obtained.

[2625]¹H-NMR (CDCl₃)δ: 1.48 (9H, s), 3.47 (6H, br), 3.76 (2H, br), 7.29(1H, m), 7.34 (1H, t, J=7.8 Hz), 7.44 (1H, dd, J=7.8, 2.0 Hz), 7.52 (2H,d, J=7.8 Hz), 7.90 (2H, d, J=7.8 Hz), 8.35 (1H, d, J=5.9 Hz).

[2626] MS (FAB) m/z: 384 (M+H)⁺.

Referential Example 35 2-[4-[(1-Piperazinyl)carbonyl]phenyl]pyridineN-oxide Hydrochloride

[2627] In dichloromethane (2.5 ml),2-[4-[[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide was dissolved. To the resulting solution, a saturated solutionof hydrochloride in ethanol (2.5 ml) was added, followed by stirring atroom temperature for 1 hour. After the solvent was distilled off underreduced pressure, water was added to the residue, whereby an aqueoussolution was obtained. Acetone was added to the aqueous solution untilthe solution became turbid. The precipitate was collected by filtrationand washed with acetone, whereby the title compound (274 mg, 81%) wasobtained.

[2628]¹H-NMR (DMSO-d₆) δ: 3.17 (4H, br s), 3.50-3.95 (4H, br), 7.43 (1H,d, J=3.9 Hz), 7.44 (1H, d, J=3.9 Hz), 7.57 (2H, d, J=8.8 Hz), 7.66 (1H,t, J=3.9 Hz), 7.92 (2H, d, J=8.8 Hz), 8.36 (1H, t, J=3.9 Hz), 9.21 (2H,br)

[2629] MS (FAB) m/z: 284 (M+H)⁺.

Referential Example 361-(tert-Butoxycarbonyl)-4-[4-(3-pyridyl)benzoyl]piperazine

[2630] In the same manner as in Referential Example 3, a re-action wasconducted using 4-(3-pyridyl)benzoic acid hydrochloride obtained inReferential Example 8 and tert-butyl-1-piperazinecarboxylate as startingmaterials, whereby the title compound was obtained.

[2631]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.35-3.85 (8H, br), 7.38 (1H, dd,J=7.8, 4.9 Hz), 7.52 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz), 7.88(1H, m), 8.62 (1H, dd, J=1.5, 4.9 Hz), 8.84 (1H, d, J=2.0 Hz).

Referential Example 373-(4-[[4-(tert-Butoxycarbonyl)piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[2632] In the same manner as in Referential Example 34, the titlecompound was obtained as a colorless solid by using1-(tert-butoxycarbonyl)-4-[4-(3-pyridyl)benzoyl]piperazine as a startingmaterial.

[2633]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.35-4.83 (8H, br), 7.38 (1H, m),7.47 (1H, m), 7.49-7.65 (4H, m), 8.23 (1H, dd, J=6.4, 1.5 Hz), 8.47 (1H,t, J=1.5 Hz).

[2634] MS (FAB) m/z: 384 (M+H)⁺.

[2635] Elementary analysis for C₂₁H₂₅N₃O₄.0.25H₂O

[2636] Calculated: C, 65.02; H, 6.63; N, 10.83.

[2637] Found: C, 65.30; H, 6.65; N, 10.43.

Referential Example 38 2-Hydroxy-4-(4-pyridyl)benzoic Acid

[2638] In water (22.5 ml) and a 47% aqueous solution of hydrobromic acid(22.5 ml), 4-amino-2-hydroxybenzoic acid (5.04 g) was dissolved. Whilethe resulting solution mixture was maintained at 5° C. or lower, anaqueous solution (water: 15.0 ml) of sodium nitrite (2.26 g) was addeddropwise thereto, followed by stirring for 30 minutes under ice cooling.The reaction mixture was added, in portions, to a solution of cuprousbromide (5.63 g) dissolved in a 47% aqueous solution of hydrobromic acid(15 ml) under ice cooling. The resulting mixture was stirred at roomtemperature for 150 minutes. Ethyl acetate was added to the reactionmixture for extraction. The organic layer so obtained was washed withwater and then dried over anhydrous sodium sulfate. The residue obtainedby distilling off the solvent under reduced pressure was purified bychromatography on a silica gel column (dichloromethane˜10%methanol—dichloromethane), whereby 4-bromo-2-hydroxybenzoic acid (5.51g) was obtained as a crudely purified product.

[2639] The crudely purified product (298 mg) was reacted as inReferential Example 6, whereby the title compound (70 mg, 21%) wasobtained.

[2640]¹H-NMR (DMSO-d₆) δ: 7.30-7.40 (2H, m), 7.78 (2H, d, J=4.4 Hz),7.92 (1H, d, J=6.3 Hz), 8.69 (2H, d, J=5.9 Hz).

[2641] MS (FAB) m/z: 216 (M+H)⁺.

Referential Example 39 4-Bromo-3-hydroxybenzoic Acid

[2642] In acetic acid (24.5 ml), 3-hydroxybenzoic acid (5.00 g) wassuspended. To the resulting suspension, a solution of bromine (1.9 ml)in acetic acid (acetic acid: 5 ml) was added dropwise under ice cooling,followed by stirring at room temperature for 33 hours. The reactionmixture was ice cooled. The crystals so precipitated were collected byfiltration and then washed with acetic acid, whereby the title compound(1.68 g, 21%) was obtained.

[2643]¹H-NMR (DMSO-d₆) δ: 7.28 (1H, dd, J=7.8, 2.0 Hz), 7.51 (1H, d,J=2.0 Hz), 7.59 (1H, d, J=8.3 Hz), 10.54 (1H, br s), 12.84 (1H, br)

Referential Example 40 Methyl 4-bromo-3-methoxybenzoate

[2644] In the same manner as in Referential Example 17, a reaction wasconducted using 4-bromo-3-hydroxybenzoic acid as a starting material,whereby the title compound was obtained.

[2645]¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 3.96 (3H, s), 7.51 (1H, dd, J=8.3,2.0 Hz), 7.55 (1H, d, J=2.0 Hz), 7.61 (1H, d, J=8.8 Hz)

Referential Example 41 3-Methoxy-4-(4-pyridyl)benzoic Acid

[2646] In the same manner as in Referential Example 7, a reaction wasconducted using methyl 4-bromo-3-methoxybenzoate and diethyl(4-pyridyl)borane. The crude product so obtained was reacted as inReferential Example 8, whereby the title compound was obtained.

[2647]¹H-NMR (CDCl₃)δ: 3.93 (3H, s), 7.65-7.75 (3H, m), 8.20 (2H, d,J=5.4 Hz), 8.94 (2H, d, J=6.3 Hz).

[2648] MS (FAB) m/z: 230 (M+H)⁺.

Referential Example 424-tert-Butoxycarbonyl-1-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine

[2649] In dichloromethane (18 ml),1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (517 mg) and6-chloro-2-naphthylsulfonyl chloride (588 mg) were dissolved under icecooling. To the resulting solution, diisopropylethylamine (0.59 ml) wasadded, followed by stirring at room temperature for 63 hours. Theresidue obtained by distilling off the solvent under reduced pressurewas purified by chromatography on a silica gel column (hexane:ethylacetate=3:1), whereby the title compound (688 mg, 71%) was obtained.

[2650]¹H-NMR (CDCl₃)δ: 1.05 (3H, t, J=7.1 Hz), 1.38 (9H, s), 2.80-4.70(9H, m), 7.55 (1H, dd, J=8.6, 2.2 Hz), 7.77 (1H, dd, J=8.6, 1.7 Hz),7.85-7.90 (3H, m), 8.33 (1H, s).

[2651] MS (FAB) m/z: 483[(M+H)⁺, Cl³⁵], 485[(M+H)⁺, Cl³⁷].

Referential Example 434-tert-Butoxycarbonyl-2ethoxycarbonyl-1-[4-(3-pyridyl)benzoyl]piperazine

[2652] In the same manner as in Referential Example 12, a reaction wasconducted using 4-(3-pyridyl)benzoic acid and1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine as starting materials,whereby the title compound was obtained.

[2653]¹H-NMR (CDCl₃) δ: 1.20-1.40 (3H, m), 1.46 (9H, s), 2.70-4.80 (8H,m), 5.35 (1H, br), 7.35-7.70 (5H, m), 7.85-7.95 (1H, m), 8.64 (2H, dd,J=4.6, 1.7 Hz), 8.86 (1H, s).

[2654] MS (FAB) m/z: 440 (M+H)⁺.

Referential Example 44 Methyl N-tert-butoxycarbonyltranexamate

[2655] To methanol (20 ml), thionyl chloride (1 ml) was added dropwiseunder ice cooling, followed by the addition of tranexamic acid (2.04 g).The resulting mixture was heated under reflux for 3 hours. The residueobtained by distilling the reaction mixture under reduced pressure waspulverized in ether and then collected by filtration, whereby colorlesscrystals (2.31 g) were obtained.

[2656] The resulting crystals (2.10 g) were dissolved in dichloromethane(40 ml), followed by the addition of N-methylmorpholine (1.2 ml). To theresulting mixture, a solution of di-tert-butyl dicarbonate (2.51 g) indichloromethane (dichloromethane: 3 ml) was added under ice cooling. Theresulting mixture was stirred at room temperature for 18 hours. Afterdiluted with dichloromethane, the reaction mixture was washed with waterand then dried over anhydrous sodium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was purified bychromatography on a silica gel column (hexane:ethyl acetate=10:1˜3:1),followed by recrystallization from a mixed solvent of hexane and ethylacetate, whereby colorless crystals (2.09 g, 65%) was obtained.

[2657]¹H-NMR (CDCl₃) δ: 0.90-1.10 (2H, m), 1.40-1.60 (12H, m), 1.80-1.90(2H, m), 2.00-2.10 (2H, m), 2.24 (1H, m), 2.98 (2H, m), 3.66 (3H, s),4.58 (1H, br).

[2658] Elementary analysis for C₁₄H₂₅NO₄

[2659] Calculated: C, 61.97; H, 9.29; N, 5.16.

[2660] Found: C, 62.15; H, 9.42; N, 5.12.

Referential Example 45trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexylmethanol

[2661] Methyl N-tert-butoxycarbonyltranexamate (1.00 g) was dissolved ina mixed solvent of tetrahydrofuran (10 ml) and methanol (2 ml). To theresulting solution, sodium borohydride (0.44 g) was added under icecooling, followed by stirring at room temperature for 24 hours. Afterthe addition of water, the reaction mixture was concentrated underreduced pressure. Ethyl acetate and dilute hydrochloric acid were addedto the concentrate. The organic layer so separated was dried overanhydrous sodium sulfate. The residue obtained by distilling off thesolvent under reduced pressure was purified by chromatography on asilica gel column in repetition (first time; dichloromethanedichloromethane:methanol=20:1, second time; hexane ethyl acetate=3:1),whereby colorless crystals (0.74 g, 82%) were obtained. A portion of thecrystals was recrystallized from a mixed solvent of hexane and ethylacetate, whereby colorless crystals were obtained.

[2662]¹H-NMR (CDCl₃)δ: 0.90-1.10 (4H, m), 1.30-1.60 (12H, m), 1.80-2.00(4H, m), 2.98 (2H, m), 3.45 (2H, d, J=6.4 Hz), 4.59 (1H, br).

[2663] Elementary analysis for C₁₃H₂₅NO₃

[2664] Calculated: C, 64.17; H, 10.35, N, 5.76.

[2665] Found: C, 64.31; H, 10.03; N, 5.74.

Referential Example 46trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexanecarboxaldehyde

[2666] In dichloromethane (5 ml),trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexylmethanol (0.20 g)was dissolved, followed by the addition of pyridinium chlorochromate(0.23 g). The resulting mixture was stirred at room temperature for 3hours. The reaction mixture was purified by chromatography on a silicagel column (hexane:ethyl acetate=3:1), whereby the title compound (0.15g, 76%) was obtained.

[2667]¹H-NMR (CDCl₃) δ: 1.00 (2H, m), 1.27 (2H, m), 1.40-1.60 (1H, m),1.44 (9H, s), 1.88 (2H, m), 2.02 (2H, m), 2.18 (1H, m), 3.00 (2H, t,J=6.4 Hz), 4.61 (1H, br), 9.62 (1H, s).

[2668] MS (FAB) m/z: 242 (M+H)⁺.

Referential Example 471-[trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexylmethyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2669] In dichloromethane (7 ml),trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexane carboxaldehyde(0.13 g) was dissolved, followed by the addition of1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (0.24g), triethylamine (78 μl) and sodium triacetoxyborohydride (0.17 g). Theresulting mixture was stirred at room temperature for 11 hours under anargon gas atmosphere. To the reaction mixture, an aqueous solution ofsodium bicarbonate was added, followed by dilution with dichloromethane.The organic layer so separated was dried over anhydrous sodium sulfate.The residue obtained by distilling off the solvent under reducedpressure was purified by chromatography on a silica gel column(hexane:ethyl acetate=2:1), whereby the title compound (0.29 g, 100%)was obtained.

[2670]¹H-NMR (CDCl₃) δ: 0.70-0.90 (4H, m), 1.30-1.50 (2H, m), 1.42 (9H,s), 1.70-1.80 (4H, m), 2.09 (2H, d, J=7.3 Hz), 2.46 (4H, m), 2.92 (2H,m), 3.08 (4H, m), 4.53 (1H, br), 7.56 (1H, dd, J=8.8, 2.0 Hz), 7.78 (1H,dd, J=8.8, 2.0 Hz), 7.80-8.00 (3H, m), 8.30 (1H, s).

[2671] MS (FAB) m/z: 536[(M+H)⁺, Cl³⁵], 538[(M+H)⁺, Cl³⁷].

Referential Example 481-[trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexylcarbonlyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2672] A reaction was conducted as in Referential Examples 11 and 12,whereby the title compound was obtained.

[2673]¹H-NMR (CDCl₃) δ: 0.80-1.00 (2H, m), 1.40-1.60 (3H, m), 1.42 (9H,s), 1.60-1.70 (2H, m), 1.70-1.90 (2H, m), 2.30 (1H, m), 2.95 (2H, m),3.07 (4H, m), 3.58 (2H, br), 3.70 (2H, br), 4.57 (1H, m), 7.58 (1H, dd,J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 1.5 Hz), 7.90-8.00 (3H, m), 8.30(1H, s).

[2674] MS (FD) m/z: 549(M⁺, Cl³⁵), 551(M⁺, Cl³⁷).

Referential Example 49N-[trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexylcarbonyl]glycineBenzyl Ester

[2675] In the same manner as in Referential Examples 11 and 12, areaction was conducted using methyl N-tert-butoxycarbonyltranexamate andglycine benzyl ester as starting materials, whereby the title compoundwas obtained.

[2676]¹H-NMR (CDCl₃) δ: 0.96 (2H, m), 1.44 (9H, s), 1.40-1.60 (3H, m),1.80-1.90 (2H, m), 1.90-2.00 (2H, m), 2.10 (1H, m), 2.98 (2H, m), 4.08(2H, d, J=4.9 Hz), 4.57 (1H, br), 5.19 (2H, s), 5.97 (1H, m), 7.30-7.40(5H, m).

[2677] Elementary analysis for C₂₂H₃₂N₂O₅

[2678] Calculated: C, 65.32; H, 7.97; N, 6.93.

[2679] Found: C, 65.05; H, 7.89; N, 7.16.

Referential Example 501-[N-trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexylcarbonyl]glycyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2680] In tetrahydrofuran (11 ml),N-[trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexylcarbonyl]glycinebenzyl ester (0.22 g) was suspended. To the resulting suspension, 10%palladium carbon (water content: about 50%, 50 mg) was added, followedby catalytic hydrogenation at normal pressure and room temperature for14 hours. After the removal of the catalyst by filtration, the solventwas distilled off under reduced pressure. The residue so obtained wasreacted as in Referential Example 12, whereby the title compound (0.32g, 98%) was obtained.

[2681]¹H-NMR (CDCl₃) δ: 0.80-1.00 (2H, m), 1.30-1.50 (3H, m), 1.43 (9H,s), 1.80-2.00 (4H, m), 2.06 (1H, m), 2.95 (2H, m), 3.10-3.20 (4H, m),3.52 (2H, m), 3.74 (2H, m), 3.94 (2H, d, J=4.4 Hz), 4.54 (1H, m), 6.40(1H, m), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.74 (1H, dd, J=8.8, 1.5 Hz),7.80-8.00 (3H, m), 8.30 (1H, s).

[2682] MS (FAB) m/z: 607 [(M+H)⁺, Cl³⁵], 609 [(M+H)⁺, Cl³⁷].

Referential Example 511-[(6-Chloronaphthalen-2-yl)sulfonyl]homopiperazine Hydrochloride

[2683] Homopiperazine (5 g) was dissolved in tetrahydrofuran (100 ml) atroom temperature. To the resulting solution,2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (12.3 g) was addedin portions, followed by stirring for 3 hours. After completion of thereaction, the solvent was distilled off. The residue was purified bychromatography on a silica gel column (10 to 20%methanol—dichloromethane), followed by the addition of 1N aqueoushydrochloric acid in ethanol. The solvent was then distilled off. Theresidue was solidified by the addition of ethanol, whereby powders (7.46g) were obtained. The resulting powders were reacted as in ReferentialExample 1, whereby the title compound was obtained.

[2684]¹H-NMR (DMSO-d₆) δ: 2.00 (2H, br s), 3.10-3.30 (4H, m), 3.30-3.50(2H, m), 3.55-3.65 (2H, m), 7.72 (1H, d, J=8.8 Hz), 7.89 (1H, d, J=8.3Hz), 8.17 (1H, d, J=8.8 Hz), 8.22-8.28 (2H, m), 8.56 (1H, s), 9.29 (2H,br s).

[2685] MS (FAB) m/z: 325 (M+H)⁺.

[2686] Elementary analysis for Cl₅HL₇ClN₂O₂S.HCl

[2687] Calculated: C, 49.89; H, 5.02; N, 7.75; Cl, 19.63.

[2688] Found: C, 49.94; H, 5.05; N, 7.47; Cl, 19.65.

Referential Example 521-[trans-4-(N-tert-Butoxycarbonylaminomethyl)cyclohexylcarbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine

[2689] In the same manner as in Referential Example 48, a reaction wasconducted using methyl N-tert-butoxycarbonyltranexamate and1-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine hydrochloride,whereby the title compound was obtained.

[2690]¹H-NMR (CDCl₃) δ: 0.80-1.00(2H, m), 1.40-1.60 (3H, m), 1.43 (9H,s), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m), 2.30-2.40 (1H, m), 2.97 (2H,m), 3.30-3.50 (4H, m), 3.60-3.80 (4H, m), 4.64 (1H, br), 7.50-7.60 (1H,m), 7.70-7.80 (1H, m), 7.80-8.00 (3H, m), 8.33 and 8.35 (1H, each s).

[2691] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁷].

Referential Example 53 Methyl4-(N-tert-butoxycarbonylaminomethyl)benzoate

[2692] In the same manner as in Referential Example 44, a reaction wasconducted using 4-aminomethylbenzoic acid as a starting material,whereby the title compound was obtained.

[2693]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.91 (3H, s), 4.37 (2H, d, J=5.4Hz), 4.92 (1H, br), 7.35 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz).

[2694] Elementary analysis for C₁₄H₁₉NO₄

[2695] Calculated: C, 63.38; H, 7.22; N, 5.28.

[2696] Found: C, 63.20; H, 7.02; N, 5.58.

Referential Example 541-[4-(N-tert-Butoxycarbonylaminomethyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2697] In the same manner as in Referential Example 48, a reaction wasconducted using methyl 4-(N-tert-butoxycarbonylaminomethyl)benzoate and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride, wherebythe title compound was obtained.

[2698]¹H-NMR (CDCl₃)δ: 1.45 (9H, s), 3.00-3.30 (4H, br), 3.40-4.00 (4H,br), 4.31 (2H, d, J=5.9 Hz), 4.90 (1H, br), 7.27 (4H, m), 7.59 (1H, dd,J=8.8, 1.5 Hz), 7.75 (1H, d, J=8.8 Hz), 7.90-8.00 (3H, m), 8.30 (1H, s).

[2699] MS (FAB) m/z: 544 [(M+H)⁺, Cl³⁵], 546 [(M+H)⁺, Cl³⁷].

Referential Example 55 Methyl3-(N-tert-butoxycarbonylaminomethyl)benzoate

[2700] Methyl 3-methylbenzoate (1.00 g) was dissolved in carbontetrachloride (10 ml), followed by the addition of N-bromosuccinic imide(1.22 g) and 2,2′-azobisisobutyronitrile (catalytic amount). Theresulting mixture was heated under reflux for 1 hour under exposure to amercury lamp. After the insoluble matter was filtered off, the residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (hexane:ethylacetate=20:1), whereby a colorless oil (1.34 g) was obtained.

[2701] The colorless oil (0.62 g) so obtained was dissolved inN,N-dimethylformamide (10 ml), followed by the addition of sodium azide(0.38 g). The resulting mixture was stirred at room temperature for 20hours. After the concentration of the reaction mixture under reducedpressure, the concentrate was diluted with ethyl acetate, washed withwater and then dried over anhydrous sodium sulfate. The residue obtainedby distilling off the solvent under reduccd pressure was dissolved intetrahydrofuran (15 ml). Triphenylphosphine (0.75 g) was added to theresulting solution, followed by stirring at an external temperature ofabout 50° C. for 5 hours. After the addition of about 28% aqueousammonia (7 ml) and stirring for further 2 hours, the reaction mixturewas concentrated under reduced pressure. The concentrate was extractedwith ether. Dilute hydrochloric acid was added to the extract to make itacidic. To the water layer so separated, a dilute aqueous solution ofsodium hydroxide was added to make it alkaline, followed by extractionwith dichloromethane. The extract was dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was dissolved in dichloromethane (7 ml). To theresulting solution, di-tert-butyl dicarbonate (0.45 g) was added underice cooling, followed by stirring at room temperature for 3 days. Theresidue obtained by distilling off the solvent under reduced pressurewas purified by chromatography on a silica gel column (hexane:ethylacetate=5:1), whereby the title compound (0.29 g, 35%) was obtained.

[2702]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 3.91 (3H, s), 4.36 (2H, d, J=5.9Hz), 4.97 (1H, br), 7.40 (1H, t, J=7.8 Hz), 7.49 (1H, d, J=7.8 Hz),7.90-8,00 (2H, m).

[2703] MS (FAB) m/z: 266 (M+H)⁺.

Referential Example 56 Methyl 4-cyanomethylbenzoate

[2704] In dichloromethane (20 ml), methyl 4-hydroxymethylbenzoate (1.00g) was dissolved, followed by the addition of triethylamine (0.9 ml).Under ice cooling, a solution of methanesulfonyl chloride (0.70 g) indichloromethane (dichloromethane: 5 ml) was added to the resultingsolution. The resulting mixture was stirred at room temperature for 15hours. After dilution with dichloromethane, the reaction mixture waswashed with water and was then dried over anhydrous sodium sulfate. Theresidue obtained by distilling off the solvent under reduced pressurewas dissolved in acetonitrile (12 ml). To the resulting solution,potassium cyanide (0.80 g) and 18-Crown-6 (0.16 g) were added, followedby stirring at room temperature for 40 hours. After concentration underreduced pressure, the concentrate was diluted with dichloromethane,washed with water and then, dried over anhydrous sodium sulfate. Theresidue obtained by distilling off the solvent under reduced pressurewas purified by chromatography on a silica gel column (dichloromethane),whereby colorless crystals (0.91 g, 86%) was obtained. A portion of theresulting crystals was recrystallized from a mixed solvent of hexane andethyl acetate, whereby colorless crystals were obtained.

[2705]¹H-NMR (CDCl₃) δ: 3.82 (2H, s), 3.93 (3H, s), 7.42 (2H, d, J=8.3Hz), 8.06 (2H, d, J=8.3 Hz).

[2706] Elementary analysis for C₁₀H₉NO₂

[2707] Calculated: C, 68.56; H, 5.18; N, 8.00.

[2708] Found: C, 68.39; H, 5.29; N, 8.08.

Referential Example 57 Methyl4-[2-(tert-butoxycarbonylamino)ethyl]benzoate

[2709] Methyl 4-cyanomethylbenzoate (0.20 g) was dissolved in a mixedsolvent of methanol (15 ml) and chloroform (0.4 ml). To the resultingsolution, platinum dioxide (33 mg) was added, followed by catalytichydrogenation at room temperature under 3 atmospheric pressure for 3hours. The catalyst was removed by filtration through Celite and thesolvent was distilled off under reduced pressure. The residue wassuspended in dichloromethane (5 ml), followed by the addition oftriethylamine (160 μl). After the addition of a solution ofdi-tert-butyl dicarbonate (0.29 g) in dichloromethane (dichloromethane:2 ml) under ice cooling, the resulting solution was stirred at roomtemperature for 13 hours. The reaction mixture was diluted withdichloromethane, washed with water and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by chromatography on a silica gel column(hexane:ethyl acetate=10:1˜5:1), whereby the title compound (0.28 g,88%) was obtained.

[2710]¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.86 (2H, t, J=6.8 Hz), 3.39 (2H,m), 3.91 (3H, s), 4.53 (1H, br), 7.27 (2H, d, J=8.3 Hz), 7.98 (2H, d,J=8.3 Hz).

[2711] Elementary analysis for C₁₅H₂₁NO₄

[2712] Calculated: C, 64.50; H, 7.58; N, 5.01.

[2713] Found: C, 64.43; H, 7.35; N, 4.97.

Referential Example 581-[4-[2-(tert-Butoxycarbonylamino)ethyl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2714] In the same manner as in Referential Example 48, the titlecompound was obtained using methyl4-[2-(tert-butoxycarbonylamino)ethyl]benzoate and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[2715]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.79 (2H, t, J=6.8 Hz), 3.10 (4H,br), 3.35 (2H, m), 3.40-4.00 (4H, br), 4.50 (1H, br), 7.18 (2H, d, J=8.3Hz), 7.24 (2H, d, J=8.3 Hz), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd,J=8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.30 (1H, s).

[2716] MS (FAB) m/z: 558 [(M+H)⁺, Cl³⁵], 560 [(M+H)⁺, Cl³⁷].

Referential Example 59 Methyl4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate

[2717] In tetrahydrofuran (50 ml), methyl 4-hydroxybenzoate (1.01 g),(3R)-1-tert-butoxycarbonyl-3-pyrrolidinol (1.36 g) andtriphenylphosphine (1.73 g) were dissolved, followed by the dropwiseaddition of a 40% solution (2.87 ml) of diethyl azodicarboxylate intoluene under ice cooling. The resulting mixture was stirred at roomtemperature for 20 hours. To the reaction mixture, ethyl acetate and a10% aqueous solution of potassium carbonate were added to separate theorganic layer. The organic layer so separated was washed with a 10%aqueous solution of potassium carbonate and water and dried overanhydrous sodium sulfate. The solvent was then distilled off underreduced pressure. The residue was purified by chromatography on a silicagel column (hexane:ethyl acetate=2:1), whereby the title compound (1.60g, 76%) was obtained.

[2718]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.00-2.20 (2H, m), 3.40-3.70 (4H,m), 3.89 (3H, s), 4.96 (1H, br s), 6.88 (2H, d, J=8.8 Hz), 7.90-8.00(2H, m)

Referential Example 604-[[(3S)-1-tert-Butoxycarbony-3-pyrrolidinyl]oxy]benzoic Acid

[2719] In the same manner as in Referential Example 11, a reaction wasconducted using methyl4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate as a startingmaterial, whereby the title compound was obtained.

[2720]¹H-NMR (CD₃OD) δ: 1.45 and 1.47 (9H, each s), 2.10-2.20 (2H, m),3.40-3.70 (4H, m), 5.00-5.10 (1H, m), 6.98 (2H, d, J=8.8 Hz), 7.97 (2H,d, J=8.8 Hz).

Referential Example 611-[4-[[(3S)-1-tert-Butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2721] In the same manner as in Referential Example 12, a reaction wasconducted using 4-[[(3S)-1-tert-butoxycarbonyl3-pyrrolidinyl]oxy]benzoicacid and 1-[(6-chloronaphthalen2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2722]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.00-2.20 (2H, m), 3.00-3.20 (4H,m), 3.40-3.80 (8H, m), 4.88 (1H, br s), 6.82 (2H, d, J=8.3 Hz),7.20-7.30 (2H, m), 7.60 (1H, dd, J=8.7, 1.9 Hz), 7.76 (1H, dd, J=8.5,1.7 Hz), 7.90-7.95 (3H, m), 8.30 (1H, s).

[2723] Elementary analysis for C₃₀H₃₄ClN₃O₆S

[2724] Calculated: C, 60.04; H, 5.71; N, 7.00.

[2725] Found: C, 60.05; H, 5.69; N, 6.80.

Referential Example 62 Methyl3-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate

[2726] In the same manner as in Referential Example 59, the titlecompound was obtained using methyl 3-hydroxybenzoate as a startingmaterial.

[2727]¹H-NMR (CDCl₃)δ: 1.45 and 1.47 (9H, each s), 2.05-2.25 (2H, m),3.40-3.70 (4H, m), 3.92 (3H, s), 4.96 (1H, br s), 7.07 (1H, d, J=7.8Hz), 7.30-7.40 (1H, m), 7.53 (1H, d, J=2.0 Hz), 7.65 (1H, m).

[2728] MS (FAB) m/z: 322 (M+H)⁺.

Referential Example 633-[[(3S)-1-tert-Butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic Acid

[2729] In the same manner as in Referential Example 11, the titlecompound was obtained using methyl3-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate as a startingmaterial.

[2730]¹H-NMR (CD₃OD) δ: 1.45 and 1.47 (9H, each s), 2.05-2.25 (2H, m),3.35-3.65 (4H, m), 5.04 (1H, br s), 7.05-7.15 (1H, m), 7.30-7.40 (1H,m), 7.53 (1H, s), 7.62 (1H, d, J=7.3 Hz).

[2731] MS (FAB) m/z: 308 (M+H)⁺.

Referential Example 641-[3-[[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2732] In the same manner as in Referential Example 12, the titlecompound was obtained using3-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic acid as astarting material.

[2733]¹H-NMR (CDCl₃) δ: 1.45 and 1.46 (9H, each s), 2.00-2.20 (2H, m),2.95-3.25 (4H, m), 3.40-3.90 (8H, m), 4.84 (1H, br s), 6.80-6.90 (3H,m), 7.20-7.30 (1H, m), 7.60 (1H, dd, J=8.8, 1.5 Hz), 7.76 (1H, dd,J=8.5, 1.7 Hz), 7.90-7.95 (3H, m), 8.30-8.35 (1H, m).

[2734] MS (FAB) m/z: 600 [(M+H)⁺, Cl³⁵], 602 [(M+H)⁺, Cl³⁷].

Referential Example 65 Methyl4-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate

[2735] In the same manner as in Referential Example 59, the titlecompound was obtained using methyl 4-hydroxybenzoate and(3S)-1-tert-butoxycarbonyl-3-pyrrolidinol as starting materials.

[2736]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.05-2.25 (2H, m), 3.40-3.70 (4H,m), 3.89 (3H, s), 4.96 (1H, br s), 6.88 (2H, d, J=8.8 Hz), 7.90-8.00(2H, m).

[2737] MS (FAB) m/z: 322 (M+H)⁺.

Referential Example 664-[[(3R)-1-tert-Butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic Acid

[2738] In the same manner as in Referential Example 11, the titlecompound was obtained using methyl4-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate as a startingmaterial.

[2739]¹H-NMR (CD₃OD) δ: 1.47 and 1.48 (9H, each s), 2.10-2.25 (2H, m),3.40-3.70 (4H, m), 4.98 (1H, br s), 6.91 (2H, d, J=8.8 Hz), 8.00-8.10(2H, m).

[2740] MS (FAB) m/z: 308 (M+H)⁺.

Referential Example 671-[4-[[(3R)-1-tert-Butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2741] In the same manner as in Referential Example 12, the titlecompound was obtained using4-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic acid as astarting material.

[2742]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.00-2.20 (2H, m), 3.00-3.20 (4H,m), 3.40-3.80 (8H, m), 4.89 (1H, br s), 6.82 (2H, d, J=8.3 Hz),7.20-7.30 (2H, m), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.74 (1H, dd, J=8.5,1.7 Hz), 7.90-7.95 (3H, m), 8.30 (1H, s).

[2743] MS (FAB) m/z: 600 [(M+H)⁺, Cl³⁵], 602 [(M+H)⁺, Cl³⁷].

Referential Example 68 Methyl3-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate

[2744] In the same manner as in Referential Example 59, the titlecompound was obtained using methyl 3-hydroxybenzoate and(3S)-1-tert-butoxycarbonyl-3-pyrrolidinol as starting materials.

[2745]¹H-NMR (CDCl₃)δ: 1.47 (9H, s), 2.05-2.25 (2H, m), 3.40-3.70 (4H,m), 3.92 (3H, s), 4.95 (1H, br s), 7.07 (1H, d, J=7.8 Hz), 7.30-7.40(1H, m), 7.50-7.55 (1H, m), 7.60-7.70 (1H, m).

[2746] MS (FAB) m/z: 322 (M+H)⁺.

Referential Example 693-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic Acid

[2747] In the same manner as in Referential Example 11, the titlecompound was obtained using methyl3-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoate as a startingmaterial.

[2748]¹H-NMR (CD₃OD) δ: 1.48 (9H, s), 2.05-2.25 (2H, m), 3.45-3.70 (4H,m), 4.97 (1H, br s), 7.10-7.15 (1H, m), 7.35-7.45 (1H, m), 7.58 (1H, s),7.70-7.75 (1H, m).

[2749] MS (FAB) m/z: 308 (M+H)⁺.

Referential Example 701-[3-[[(3R)-1-tert-Butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2750] In the same manner as in Referential Example 12, the titlecompound was obtained using3-[[(3R)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic acid as astarting material.

[2751]¹H-NMR (CDCl₃) δ: 1.45 and 1.46 (9H, each s), 2.00-2.20 (2H, m),2.95-3.25 (4H, m), 3.40-3.90 (8H, m), 4.84 (1H, br s), 6.80-6.90 (3H,m), 7.20-7.30 (1H, m), 7.60 (1H, dd, J=8.5, 1.7 Hz), 7.76 (1H, dd,J=8.5, 2.0 Hz), 7.90-7.95 (3H, m), 8.30-8.35 (1H, m).

[2752] MS (FAB) m/z: 600 [(M+H)⁺, Cl³⁵), 602 [(M+H)⁺, Cl³⁷].

Referential Example 71 4-(2-Amino-5-pyrimidyl)benzoic Acid

[2753] In the same manner as in Referential Example 2, the titlecompound was obtained using 2-amino-5-bromopyrimidine as a startingmaterial.

[2754]¹H-NMR (DMSO-d₆) δ: 7.81 (2H, d, J=8.8 Hz), 8.00 (2H, d, J=8.8Hz), 8.84 (2H, s).

[2755] MS (FAB) m/z: 216 (M+H)⁺.

Referential Example 721-tert-Butoxycarbonyl-4-[(methoxycarbonyl)methylene]piperidine

[2756] In tetrahydrofuran (40 ml), methyl dimethylphosphonoacetate (1.8ml) was dissolved. To the resultLng solution, 60% oily sodium hydride(450 mg) was added under ice cooling, followed by stirring under thesame condition. After the addition of a solution of1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran(tetrahydrofuran: 10 ml) and stirring at room temperature for 30minutes, the reaction mixture was diluted with ethyl acetate. To thediluted solution, 2N hydrochloric acid was added. The organic layer wasseparated, washed with a saturated aqueous solution of sodiumbicarbonate and saturated aqueous NaCl solution, and dried overanhydrous sodium sulfate. The solvent was then distilled off underreduced pressure. The residue was purified by chromatography on a silicagel column (hexane:ethyl acetate=6:1), whereby the title compound (2.35g, 92%) was obtained.

[2757]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.28 (2H, t, J=5.9 Hz), 2.94 (2H,t, J=5.9 Hz), 3.48 (2H, t, J=5.9 Hz), 3.50 (2H, t, J=5.9 Hz), 3.70 (3H,s), 5.72 (1H, s).

[2758] Elementary analysis for C₁₃H₂₁NO₄

[2759] Calculated: C, 61.16; H, 8.29; N, 5.49.

[2760] Found: C, 61.14; H, 8.34; N, 5.20.

Referential Example 73 Methyl(1-tert-butoxycarbonylpiperidin-4-yl)acetate

[2761] In ethanol (10 ml),1-tert-butoxycarbonyl-4[(methoxycarbonyl)methylene]piperidine (875 mg)was dissolved, followed by the addition oL 10% palladium carbon (watercontent: about 50%, 730 mg). The resulting mixture was subjected tocatalytic hydrogenation under normal pressure at room temperature for 3days. After the removal of the catalyst by filtration, the solvent wasdistilled off under reduced pressure, whereby the title compound (871mg, 99%) was obtained.

[2762]¹H-NMR (CDCl₃) δ: 1.16 (2H, m), 1.45 (9H, s), 1.65 (2H, m), 1.93(1H, m), 2.25 (2H, d, J=6.8 Hz), 2.72 (2H, br), 3.68 (3H, s), 4.08 (2H,br).

[2763] MS (FAB) m/z: 258 (M+H)⁺.

Referential Example 74 (1-tert-Butoxycarbonylpiperidin4-yl)acetic Acid

[2764] In the same manner as in Referential Example 11, the titlecompound was obtained using methyl(1-tert-butoxycarbonylpiperidin-4-yl)acetate as a starting material.

[2765]¹H-NMR (CDCl₃) δ: 1.18 (2H, m), 1.45 (9H, s), 1.73 (2H, m), 1.94(1H, m), 2.29 (2H, d, J=6.8 Hz), 2.72 (2H, m), 4.10 (2H, br).

[2766] MS (EI) m/z: 243 M⁺.

Referential Example 751-[(1-tert-Butoxycarbonylpiperidin-4-yl)acetyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2767] In the same manner as in Referential Example 12, a reaction wasconducted using (1-tert-butoxycarbonylpiperidin4-yl)acetic acid anu1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2768]¹H-NMR (CDCl₃) δ: 1.05 (2H, m), 1.43 (9H, s), 1.63 (2H, m), 1.91(1H, m), 2.14 (2H, d, J=6.8 Hz), 2.66 (2H, m), 3.07 (4H, br s), 3.56(2H, br s), 3.67 (2H, br s), 4.02 (2H, br), 7.58 (1H, dd, J=8.8, 2.0Hz), 7.75 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 7.93 (1H, d, J=8.8Hz), 7.92 (1H, s), 8.30 (1H, s).

[2769] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

Referential Example 76 3-(1-tert-Butoxycarbonylpiperidin-4-yl)propionicAcid

[2770] A reaction was conducted using ethyl1-tert-butoxycarbonylisonipecotinate and diisobutylaluminum hydride,whereby the corresponding aldehyde derivative was obtained. Theresulting derivative was treated as in Referential Examples 72, 73 and74, whereby the title compound was obtained.

[2771]¹H-NMR (CDCl₃) δ: 1.10 (2H, m), 1.41 (1H, m), 1.45 (9H, s), 1.60(2H, q, J=7.8 Hz), 1.66 (2H, m), 2.39 (2H, t, J=7.8 Hz), 2.67 (2H, m),4.09 (2H, br).

[2772] MS (FAB) m/z: 258 (M+H)⁺.

Referential Example 771-[3-(1-tert-Butoxycarbonylpiperidin-4-yl]propionyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2773] In the same manner as in Referential Example 12, a reaction wasconducted using 3-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acidand 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2774]¹H-NMR (CDCl₃) δ: 1.04 (2H, m), 1.35 (1H, m), 1.44 (9H, s), 1.47(2H, q, J=7.8 Hz), 1.57 (2H, m), 2.24 (2H, t, J=7.8 Hz), 2.61 (2H, m),3.07 (4H, br s), 3.56 (2H, br s), 3.71 (2H, br s), 4.04 (2H, br), 7.58(1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.90 (1H, d,J=8.8 Hz), 7.91 (1H, s), 7.92 (1H, d, J=8.8 Hz), 8.30 (1H, s).

[2775] MS (FAB) m/z: 550 [(M+H)⁺, Cl³⁵], 552 [(M+H)⁺, Cl³⁷].

Referential Example 78 (E)-3-(4-Pyridyl)acrylic Acid

[2776] In the same manner as in Referential Examples 72 and 74, thetitle compound was obtained using isonicotinic aldehyde as a startingmaterial.

[2777]¹H-NMR (DMSO-d₆) δ: 6.79 (1H, d, J=16.6 Hz), 7.56 (1H, d, J=16.6Hz), 7.66 (2H, d, J=5.9 Hz), 8.62 (2H, d, J=5.9 Hz), 12.72 (1H, br s).

[2778] MS (EI) m/z: 149M+.

Referential Example 79 1-Methoxycarbonyl-3-pyrroline

[2779] In dichloromethane (20 ml), 3-pyrroline (1.1 ml) was dissolved,followed by the addition of triethylamine (2.6 ml) and methylchloroformate (1.2 ml) under ice cooling. The resulting mixture wasstirred at room temperature for 17 hours. The residue obtained bydistilling the reaction mixture under reduced pressure was purified bychromatography on a silica gel column (hexane:ethyl acetate=4:1),whereby the title compound (0.95 g, 52%) was obtained.

[2780]¹H-NMR (CDCl₃) δ: 3.73 (3H, s), 4.00-4.20 (4H, m), 5.70-5.90 (2H,m).

Referential Example 80 Methyl 4-trifluoromethanesulfonyloxybenzoate

[2781] In dichloromethane (20 ml), methyl 4-hydroxybenzoate (1.99 g) wasdissolved, followed by the addition of pyridine (2.4 ml) andtrifluoromethanesulfonic anhydride (3.0 ml) under ice cooling. Afterstirring at room temperature for 6 hours, the reaction mixture was addedwith pyridine (1.5 ml) and trifluoromethanesulfonic anhydride (1.0 ml)again. The resulting mixture was stirred for 5 hours. Dichloromethaneand an aqueous solution of sodium bicarbonate were added to the reactionmixture. The organic layer so separated was washed with a 10% aqueouscitric acid solution and saturated aqueous NaCl solution and dried overanhydrous sodium sulfate. The residue obtained by distilling off thesolvent under reduced pressure was purified by chromatography on asilica gel column (5% ethyl acetate hexane), whereby the title compound(3.22 g, 86%) was obtained.

[2782]¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 7.36 (2H, d, J=8.8 Hz), 8.15 (2H,d, J=8.8 Hz).

[2783] MS (FAB) m/z: 285 (M+H)⁺.

Referential Example 81 Methyl4-(1-methoxycarbonylpyrrolidin-3-yl)benzoate

[2784] In N,N-dimethylformamide (25 ml), methyl4-trifluoromethanesulfonyloxybenzoate (1.05 g),1-methoxycarbonyl-3-pyrroline (1.0 g), lithium chloride (0.51 g),palladium (II) acetate (53 mg) and tri(2-furyl)phosphine (100 mg) weredissolved, followed by the addition of diisopropylethylamine (2.8 ml).Under an argon gas atmosphere, the resulting mixture was stirred at 90°C. for 11 hours and then, at 100° C. for 7 hours. The residue obtainedby distilling off the solvent under reduced pressure was added withdichloromethane and water. The organic layer so separated was washedwith water and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=9:1˜5:1).The purified product was dissolved in methanol (30 ml), followed by theaddition of 10% palladium carbon (water content: about 50%, 186 mg) andammonium formate (197 mg). The resulting mixture was heated under refluxfor 2 hours. After the removal of the catalyst by filtration, thesolvent was distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column (10% ethylacetate—toluene), whereby the title compound (241 mg, 25%) was obtained.

[2785]¹H-NMR (CDCl₃) δ: 1.95-2.10 (1H, m), 2.25-2.35 (1H, m), 3.3-03.35(4H, m), 3.55-3.75 (1H, m), 3.72 and 3.73 (3H, each s), 3.80-3.90 (1H,m), 3.91 (3H, s), 7.30 (2H, d, J=3.8 Hz), 8.00 (2H, d, J=8.3 Hz).

[2786] MS (FAB) m/z: 264 (M+H)⁺.

Referential Example 82 4-(1-tert-Butoxycarbonylpyrrolidin-3-yl)benzoicAcid

[2787] In methanol (10 ml), methyl4-(1-methoxycarbonylpyrrolidin-3-yl)benzoate (0.24 g) was dissolved.

[2788] The resulting solution was added with 8N hydrochloric acid (30ml), followed by heating under reflux for 40 hours. The residue obtainedby distilling off the solvent under reduced pressure was dissolved inN,N-dimethylformamide (30 ml). To the resulting solution,2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.30 g) and thendiisopropylethylamine (0.40 ml) were added, followed by stirring at roomtemperature for 15 hours. The residue obtained by distilling off thesolvent under reduced pressure was distributed in ethyl acetate and a10% aqueous citric acid solution. The organic layer so separated waswashed with saturated aqueous NaCl solution and dried over anhydroussodium sulfate. The solvent was then distilled off under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (dichloromethane 10% methanol—dichloromethane), whereby the titlecompound (234 mg) was obtained.

[2789]¹H-NMR (CDCl₃) δ: 1.48 (9H, m), 1.90-2.00 (1H, m), 2.20-2.30 (1H,m), 3.20-3.90 (5H, m), 7.20-7.30 (2H, m), 8.00-8.10 (2H, m).

[2790] MS (EI) m/z: 291M⁺.

Referential Example 831-[4-(3RS)-1-tert-Butoxycarbonylpyrrolidin-3-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2791] In the same manner as in Referential Example 12, a reaction wasconducted using 4-(1-tert-butoxycarbonylpyrrolidin-3-yl)benzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2792]¹H-NMR (CDCl₃) δ: 1.47 and 1.60 (9H, each s), 1.80-2.00 (1H, m),2.10-2.20 (1H, m), 3.00-4.00 (13H, m), 7.10-7.30 (4H, m), 7.55-7.65 (1H,m), 7.70-7.80 (1H, m), 7.85-8.00 (3H, m), 8.30 (1H, s).

Referential Example 84 (3S)-3-Amino-1-tert-butoxycarbonylpyrrolidine

[2793] In the same manner as in Referential Example 55, the titlecompound was obtained using(3R)-1-tert-butoxycarbonyl-3-methansulfonyloxypyrrolidine (1.50 go as astarting material.

[2794]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.98-2.11 (2H, m), 2.95-3.10 (1H,m), 3.26-3.60 (4H, m).

[2795] MS (FAB) m/z: 187 (M+H)⁺.

Referential Example 85(3S)-3-[(6-Chloronaphthalen-2-yl)sulfonamide]pyrrolidinetrifluoroacetate

[2796] In the same manner as in Referential Example 1, a reaction wasconducted using (3S)-3-amino-1-tert-butoxycarbonylpyrrolidine as astarting material, whereby the title compound was obtained.

[2797]¹H-NMR (DMSO-d₆) δ: 1.69-1.80 (1H, m), 1.88-1.99 (1H, m),2.95-3.28 (4H, m), 3.75-3.84 (1H, m), 7.71 (1H, m), 7.91 (1H, m),8.10-8.30 (4H, m), 8.53 (1H, s), 8.91 (1H, br s), 9.06 (1H, br s).

Referential Example 86(3S)-3-Amino-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine

[2798] In trifluoroacetic acid,(3R)-1-tert-butoxycarbonyl-3-methanesulfonyloxypryrrolidine wasdissolved. After the resulting solution was concentrated under reducedpressure, diethyl ether was added to the concentrate, followed by theremoval of the supernatant. The residue was reacted as in ReferentialExample 1, whereby the corresponding sulfonamide derivative was obtainedas a crude product. The crude product was subjected to azide formationand reduction as in Referential Example 55, whereby the title compoundwas

[2799]¹H-NMR (DMSO-d₆) δ: 1.38-1.53 (3H, m), 1.72-1.83 (1H, m),2.81-2.89 (1H, m), 3.20-3.39 (4H, m), 7.69 (1H, dd, J=8.8, 1.9 Hz), 7.87(1H, d, J=8.8 Hz), 8.12 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.26 (1H, d,J=8.8 Hz), 8.39 (1H, s).

[2800] MS (FAB) m/z: 311 [(M+H)⁺, Cl³⁵], 313 [(M+H)⁺, Cl³⁷].

Referential Example 87 4-Benzylamino-1-tert-butoxycarbonylpiperidine

[2801] In dichloromethane (500 ml), 1-tert-butoxycarbonyl-4-piperidione(7.00 g) was dissolved, followed by the addition of benzylamine (4.03ml) and sodium triacetoxyborohydride (11.91 g). The resulting mixturewas stirred overnight at room temperature. After the reaction mixturewas concentrated under reduced pressure, the residue was dissolved inethyl acetate. The resulting mixture was washed with water and saturatedaqueous NaCl solution and then dried over anhydrous sodium sulfate. Thesolvent was then distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column (hexane:ethylacetate=1:1), whereby the title compound (7.46 g, 76%) was obtained.

[2802]¹H-NMR (CDCl₃) δ: 1.24-1.37 (2H, m), 1.45 (9H, s), 1.80-1.90 (2H,m), 2.62-2.70 (1H, m), 2.75-2.85 (1H, m), 2.98-3.07 (1H, m), 3.78-3.90(3H, m), 3.95-4.10 (1H, m), 7.21-7.34 (5H, m).

[2803] MS (FD) m/z: 290M⁺.

Referential Example 88 4-Amino-1-tert-butoxycarbonylpiperidine Acetate

[2804] In methanol (2 ml) and acetic acid (30 ml),4-benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) was dissolved,followed by the addition of 10% palladium carbon (water content: about50%, 3.06 g). The resulting mixture was subjected to catalytichydrogenation overnight under medium pressure (3 atmospheric pressure).After the removal of the catalyst by filtration, the filtrate wasdistilled off under reduced pressure. The residue was solidified inethyl acetate, whereby the title compound (2.23 g, 57%) was obtained.

[2805]¹H-NMR (DMSO-d₆) δ: 1.10-1.23 (2H, m), 1.39 (9H, s), 1.69-1.77(2H, m), 1.80 (3H, s), 2.50 (2H, s), 2.67-2.88 (2H, m), 3.80-3.90 (1H,m).

[2806] MS (FAB) m/z: 201(M+H)⁺.

[2807] Elementary analysis for C₁₀H₂₀N₂O₂.CH₃CO₂H

[2808] Calculated: C, 53.16; H, 9.37; N, 10.33.

[2809] Found: C, 53.51; H, 9.10; N, 9.93.

Referential Example 894-[(6-Chloronaphthalen-2-yl)sulfonamido]piperidine Trifluoroacetate

[2810] In the same manner as in Referential Example 1, the titlecompound was obtained using 4-amino-1-tert-butoxycarbonylpiperidineacetate and 6-chloro-2-naphthylsulfonyl chloride as starting materials.

[2811]¹H-NMR (DMSO-d₆) δ: 1.47-1.60 (2H, m), 1.68-1.78 (2H, m),2.81-2.95 (2H, m), 3.10-3.20 (2H, m), 3.29-3.40 (1H, m), 7.70 (1H, dd,J=8.8, 2.0 Hz), 7.91 (1H, dd, J=8.8, 2.0 Hz), 8.11-8.15 (2H, m), 8.21(1H, s), 8.31 (1H, br s), 8.50 (1H, s), 8.55 (1H, br s).

[2812] MS (FAB) m/z: 325 [(M+H)⁺, Cl^(35], 327) [(M+H)⁺, Cl³⁷].

Referential Example 90 Ethyl(1RS)-4-trifluoromethanesulfonyloxy-3-cyclohexenecarboxylate

[2813] Diisopropylamine (0.99 ml) was dissolved in tetrahydrofuran (50ml), followed by the dropwise addition of nbutyl lithium (a 1.59M hexanesolution, 3.70 ml) at −78° C. After the dropwise addition of ethyl4-oxocyclohexanecarboxylate (1.00 g) dissolved in tetrahydrofuran (5 ml)to the reaction mixture and stirring for 15 minutes,N-phenyltrifluoromethanesulfonimide (2.10 g) dissolved intetrahydrofuran (5 ml) was added dropwise to the reaction mixture. Thereaction mixture was heated to 0° C., stirred for one hour and thenconcentrated under reduced pressure. The residue was purified bychromatography on a neutral alumina column (hexane:ethyl acetate=9:1),whereby the title compound (838 mg, 47%) was obtained.

[2814]¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.3 Hz), 1.88-l.99 (1H, m),2.10-2.18 (1H, m), 2.38-2.50 (4H, m), 2.55-2.64 (1H, m), 4.16 (2H, q,J=7.3 Hz), 5.77 (1H, br s).

Referential Example 91 Ethyl(1RS)-4-(4-pyridyl)-3-cyclohexenecarboxylate

[2815] In the same manner as in Referential Example 7, a reaction wasconducted using ethyl(1RS)-4-trifluoromethanesulfonyloxy-3-cyclohexenecarboxylate as astarting material, whereby the title compound was obtained.

[2816]¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.3 Hz), 1.80-1.91 (1H, m),2.19-2.25 (1H, m), 2.40-2.57 (4H, m), 2.59-2.67 (1H, m), 4.17 (2H, q,J=7.3 Hz), 6.36 (1H, br s), 7.26 (2H, dd, J=4.9, 1.5 Hz), 8.53 (2H, dd,J=4.9, 1.5 Hz).

[2817] MS (FAB) m/z: 232 (M+H)⁺.

Referential Example 92 (1RS)-4-(4-Pyridyl)-3-cyclohexenecarboxylic acid

[2818] In the same manner as in Referential Example 8, a reaction wasconducted using ethyl (1RS)-4-(4-pyridyl)-3-cyclohexenecarboxylate as astarting material, the title compound was obtained.

[2819]¹H-NMR (DMSO-d₆) δ: 1.70-1.82 (1H, m), 2.10-2.19 (1H, m),2.42-2.65 (5H, m), 6.99 (1H, br s), 8.02 (2H, d, J=6.8 Hz), 8.80 (2H, d,J=6.8 Hz).

[2820] MS (FAB) m/z: 204 (M+H)⁺.

Referential Example 93 cis-, trans-4-(4-Pyridyl)cyclohexanecarboxylicAcid

[2821] In the same manner as in Referential Example 73, the titlecompound was obtained using (1RS)-4-(4-pyridyl]-3-cyclohexenecarboxylicacid as a starting material.

[2822] MS (FAB) m/z: 206 (M+H)⁺.

Referential Example 944-(1-tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)benzoic Acid

[2823] In 1,2-dimethoxyethane (30 ml),4-(1-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine(Synthesis, 993, 1991) (3.59 g) was dissolved, followed by the additionof 4-carboxyphenylboric acid (3.60 g), lithium chloride (1.38 g),tetrakistriphenylphosphine palladium (0.62 g) and an aqueous solution ofsodium carbonate (2M, 16.3 ml). The resulting mixture was heated underreflux for 2 hours under an argon gas atmosphere. To the reactionmixture, 1N hydrochloric acid was added. The resulting mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(dichloromethane˜dichloromethane:methanol=100:1). The purified productwas pulverized and washed in a mixed solvent of hexane and ethyl acetate(hexane:ethyl acetate=5:1), whereby the title compound (462 mg, 14%) wasobtained.

[2824]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.56 (2H, br s), 3.66 (2H, m),4.12 (2H, br s), 6.19 (1H, br s), 7.47 (2H, d, J=8.3 Hz), 8.07 (2H, d,J=8.3 Hz).

[2825] MS (FAB) m/z: 304 (M+H)⁺.

Referential Example 95 4-(1-tert-Butoxycarbonylpiperidin-4-yl)benzoicacid

[2826] In the same manner as in Referential Example 73, the titlecompound was obtained by using4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid asa starting material.

[2827]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.60-1.71 (2H, m), 1.80-1.89 (2H,m), 2.69-2.90 (3H, m), 4.20-4.35 (2H, m), 7.31 (2H, d, J=8.3 Hz), 8.05(2H, d, J=8.3 Hz).

[2828] MS (FAB) m/z: 306 (M+H)⁺.

Referential Example 961-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2829] In the same manner as in Referential Example 12, a reaction wasconducted using4-(1-tert-butoxycarbonyl1,2,3,6-tetrahydropyridin-4-yl)benzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2830]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.48 (2H, br s), 3.10 (4H, br),3.62 (2H, t, J=5.9 Hz), 3.70 (4H, br), 4.08 (2H, br s), 6.05 (1H, br s),7.25 (2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.3 Hz), 7.59 (1H, dd, J=8.8, 2.0Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.90

[2831] MS (FAB) m/z: 596 [(M+H)⁺, Cl³⁵], 598 [(M+H)⁺, Cl³⁷].

Referential Example 971-[4-(1-tert-Butoxycarbonylpiperidin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2832] In the same manner as in Referential Example 12, a reaction wasconducted using 4-(1-tert-butoxycarbonylpiperidin-4-yl)benzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2833]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.49-1.63 (2H, m), 1.72-1.80 (2H,m), 2.59-2.68 (1H, m), 2.71-2.86 (2H, m), 2.92-3.30 (4H, m), 3.45-4.95(4H, m), 4.16-4.31 (2H, m), 7.18 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.3Hz), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz),7.90-7.94 (3H, m), 8.30 (1H, s).

[2834] MS (FAB) m/z: 598 [(M+H)⁺, Cl³⁵], 600 [(M+H)⁺, Cl³⁷].

Referential Example 98 (3RS)-3-Amino-1-tert-butoxycarbonylpyrrolidine

[2835] In methanol (30 ml), 3-aminopyrrolidine (0.54 g) was dissolvedunder ice cooling, followed by the addition of diisopropylethylamine(720 μl) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.84g). The resulting mixture was gradually heated to room temperature andstirred for 11 hours. The residue obtained by distilling off the solventunder reduced pressure was purified by chromatography on a silica gelcolumn (dichloromethane˜5% methanol—dichloromethane), whereby the titlecompound (0.59 g, 94%) was obtained.

[2836]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.0-2.3 (2H, m), 3.1-4.0 (5H, m).

Referential Example 99(3RS)-1-tert-Butoxycarbonyl-3-[(6-chloronaphthalen-2-yl)sulfonamide]pyrrolidine

[2837] In the same manner as in Referential Example 1, the titlecompound was obtained using(3RS)-3-amino-1-tert-butoxycarbonylpyrrolidine as a starting material.

[2838]¹H-NMR (CDCl₃) δ: 1.37 (9H, s), 1.60-2.10 (2H, m), 3.00-3.50 (4H,m), 3.88 (1H, br), 4.96 (1H, br), 7.50-7.60 (1H, m), 7.80-7.90 (4H, m),8.43 (1H, s).

[2839] MS (FAB) m/z: 411 [(M+H)⁺, Cl³⁵], 413 [(M+H)⁺, Cl³⁷].

Referential Example 100(3RS)-1-tert-Butoxycarbonyl-3[4-(4-pyridyl)benzamide]pyrrolidine

[2840] In the same manner as in Referential Example 12, the titlecompound was obtained using(3RS)-3-amino-1-tert-butoxycarbonylpyrrolidine and 4-(4-pyridyl)benzoicacid as starting materials.

[2841]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.90-2.10 (1H, m), 2.20-2.30 (1H,m), 3.30-3.40 (1H, m), 3.40-3.60 (2H, m), 3.70-3.80 (1H, m), 4.65-4.75(1H, m), 6.25-6.35 (1H, m), 7.52 (2H, d, J=5.9 Hz), 7.71 (2H, d, J=8.3Hz), 7.88 (2H, d, J=8.3 Hz),

[2842] MS (FAB) m/z: 368 (M+H)⁺.

Referential Example 101 6-Chloro-N-methoxy-N-methylnicotinamide

[2843] Under ice cooling, 6-chloronicotinic acid (5.00 g) was suspendedin dichloromethane (150 ml), followed by the addition of a catalyticamount of N,N-dimethylformamide and oxalyl chloride (5.30 ml). Theresulting mixture was stirred at room temperature for 23 hours. Theresidue obtained by concentrating the reaction mixture was dissolved indichloromethane (100 ml), followed by the addition ofN,O-dimethylhydroxylamine hydrochloride (6.18 g) and triethylamine (13.3ml) under ice cooling. After stirring at room temperature for 6 hours,the reaction mixture was diluted with dichloromethane (150 ml), washedwith a saturated aqueous solution of sodium bicarbonate, water andsaturated aqueous NaCl solution and then dried over anhydrous magnesiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(hexane:ethyl acetate=2:1), whereby the title compound (6.08 g, 96%) wasobtained.

[2844]¹H-NMR (CDCl₃) δ: 3.39 (3H, s), 3.56 (3H, s), 7.39 (1H, d, J=8.3Hz), 8.03 (1H, dd, J=8.3, 2.4 Hz), 8.78 (1H, d, J=2.4 Hz).

Referential Example 102 6-Chloronicotinaldehyde

[2845] In tetrahydrofuran (8 ml),6-chloro-N-methoxy-N-methylnicotinamide (500 mg) was dissolved, followedby the dropwise addition of diisobutylaluminum hydride (a 0.95M hexanesolution, 2.88 ml) at −78° C. in an argon gas atmosphere. The resultingmixture was stirred for 3 hours and then, at room temperature, for 2hours. After the reaction mixture was cooled to −20° C., saturatedaqueous NaCl solution (2 ml) was added thereto, followed by stirring for30 minutes. The insoluble matter was filtered off. The residue waswashed with ethyl acetate. The filtrate and the washing were combinedtogether. The mixture was washed with saturated aqueous NaCl solutionand dried over anhydrous sodium sulfate. The solvent was then distilledoff under reduced pressure, whereby the title compound (346 mg, 98%) wasobtained as a crude product. The product was provided for the subsequentreaction without purification.

[2846]¹H-NMR (CDCl₃) δ: 7.52 (1H, d, J=8.3 Hz), 8.14 (1H, dd, J=8.3, 2.2Hz), 8.87 (1H, d, J=2.2 Hz), 10.10 (1H, s).

Referential Example 1031-tert-Butoxycarbonyl-4-methanesulfonylpiperazine

[2847] In dichloromethane (40 ml), N-tert-butoxycarbonylpiperazine (2.00g) was dissolved, followed by the addition of triethylamine (1.78 ml).To the resulting solution, methanesulfonyl chloride (0.91 ml) was addeddropwise under ice cooling. After stirring for one hour under icecooling, the reaction mixture was diluted with dichloromethane (20 ml),washed with a 5% aqueous citric acid solution, water and saturatedaqueous NaCl solution and dried over anhydrous magnesium sulfate. Theresidue obtained by distilling off the solvent under reduced pressurewas recrystallized from a mixed solvent of ethyl acetate and hexane,whereby the title compound (2.58 g, 91%) was obtained.

[2848]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.79 (3H, s), 3.19 (4H, t, J=5.1Hz), 3.55 (4H, t, J=5.1 Hz).

Referential Example 1041-tert-Butoxycarbonyl-4-[[(2RS)₂-(6-chloropyridin-3-yl)-2-hydroxyethyl]sulfonyl]piperazine

[2849] In tetrahydrofuran (8 ml),1-tert-butoxycarbonyl-4-methanesulfonylpiperazine (838 mg) wasdissolved, followed by the addition of tert-butyl lithium (a 1.7Mpentane solution, 1.72 ml) at −78° C. in an argon gas atmosphere. Theresulting mixture was stirred for 2 hours. After the dropwise additionof a solution of 6-chloronicotinaldehyde (346 mg) in tetrahydrofuran(tetrahydrofuran: 4 ml) and stirring at −78° C. for 3 hours, thereaction mixture was added with isopropanol (1 ml). The resultingmixture was heated to room temperature and diluted with ethyl acetate.The diluted solution was washed with water and saturated aqueous NaClsolution and dried over anhydrous sodium sulfate. The residue obtainedby distilling off the solvent under reduced pressure was recrystallizedfrom ethyl acetate, whereby the title compound (532 mg, 54%) wasobtained.

[2850]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 3.11 (1H, dd, J=14.1, 2.2 Hz),3.21 (1H, dd, J=14.1, 9.8 Hz), 3.23-3.33 (4H, m), 3.52-3.57 (4H, m),3.70 (1H, br s), 5.37 (1H, br), 7.36 (1H, d, J=8.3 Hz), 7.72 (1H, dd,J=8.3, 2.4 Hz), 8.41 (1H, d, J=2.4 Hz).

[2851] MS (FAB) m/z: 405 (M+H)⁺.

Referential Example 1051-tert-Butoxycarbonyl-4-[[(E)-2-(6-chloropyridin-3-yl)ethylene]sulfonyl]piperazine

[2852] In dichloromethane (10 ml),1-tert-butoxycarbonyl-4[[(2RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]sulfonyl]piperazine(465 mg) was dissolved, followed by the addition of N-methylmorpholine(0.152 ml) and N,N-dimethyl4-aminopyridine (14.1 mg). Under an argonatmosphere, ptoluenesulfonyl chloride (263 mg) was added under icecooling.

[2853] After stirring at room temperature for 2 hours,N,N-dimethyl-4-aminopyridine (141 mg) was added further and theresulting mixture was stirred at room temperature for 3 hours. Afterdilution with dichloromethane (20 ml), the reaction mixture was washedwith a saturated aqueous solution of sodium bicarbonate, water andsaturated aqueous NaCl solution and then dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(dichloromethane:methanol=100:1), whereby the title compound (414 mg,93%) was obtained.

[2854]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.19 (4H, br), 3.55 (4H, br), 6.73(1H, d, J=15.6 Hz), 7.40 (1H, d, J=8.3 Hz), 7.43 (1H, d, J=15.6 Hz),7.76 (1H, dd, J=8.3, 2.5 Hz), 8.50 (1H, d, J=2.5 Hz).

[2855] Elementary analysis for C₁₆H₂₂ClN₃O₃S

[2856] Calculated: C, 49.54; H, 5.72; N, 10.83; Cl, 9.14; S, 8.27.

[2857] Found: C, 49.54; H, 5.73; N, 10.63; Cl, 9.44; S, 8.15.

Referential Example 1061-(4-Bromo-2-methylbenzoyl)-4[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[2858] In the same manner as in Referential Example 12, a reaction wasconducted using 4-bromo-2-methylbenzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[2859]¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.80-4.10 (8H, m), 6.89 (1H, d,J=8.3 Hz), 7.30 (1H, dd, J=8.3, 2.0 Hz), 7.35 (1H, d, J=2.0 Hz), 7.60(1H, dd, J=8.8, 2.0 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.90-7.95 (3H,m), 8.30 (1H, br s).

[2860] MS (FAB) m/z: 507 [(M+H)⁺, Br⁷⁹], 509 [(M+H)⁺, Br⁸¹].

Referential Example 107 3-Methyl-4-(4-pyridyl)benzoic Acid Hydrochloride

[2861] In the same manner as in Referential Example 6, a reaction wasconducted using 4-bromo-3-methylbenzoic acid as a starting material,whereby the title compound was obtained.

[2862]¹H-NMR (DMSO-d₆) δ: 2.36 (3H, s), 7.50 (1H, d, J=7.8 Hz), 7.92(1H, d, J=7.8 Hz), 7.97 (1H, s), 8.08 (2H, d, J=6.4 Hz), 8.99 (2H, d,J=6.4 Hz).

[2863] MS (FAB) m/z: 214 (M+H)⁺.

Referential Example 108 4-(2-Methyl-4-pyridyl)benzoic Acid Hydrochloride

[2864] In the same manner as in Referential Example 2, a reaction wasconducted using 4-bromo-2-methylpyridine as a starting material, wherebythe title compound was obtained.

[2865]¹H-NMR (DMSO-d₆) δ: 2.81 (3H, s), 8.10-8.16 (4H, m), 8.23 (1H, dd,J=6.4, 1.5 Hz), 8.36 (1H, d, J=1.5 Hz), 8.85 (1H, d, J=6.4 Hz).

[2866] MS (FAB) m/z: 214 (M+H)⁺.

Referential Example 109 1,4-Dibenzyl-2-methoxycarbonylmethylpiperazine

[2867] In toluene (250 ml), N,N′-dibenzylethylenediamine (12 ml) andtriethylamine (12 ml) were dissolved, followed by the dropwise additionof methyl 3-bromocrotonate (7.0 ml) under ice cooling. The resultingmixture was stirred at room temperature for 24 hours. After the additionof triethylamine (2.0 ml), the resulting mixture was stirred at roomtemperature for 71 hours. The insoluble matter was filtered off and thefiltrate was distilled under reduced pressure. The residue was addedwith 10% hydrochloric acid (300 ml) and crystals so precipitated wereremoved by filtration. Ethyl acetate was added to the filtrate.Potassium carbonate was added to the water layer so separated to make italkaline. Ethyl acetate was added to the resulting mixture. The organiclayer so separated was washed with saturated aqueous NaCl solution anddried over anhydrous potassium carbonate. The solvent was then distilledoff under reduced pressure. The residue was purified by chromatographyon a silica gel column (hexane:ethyl acetate=4:1), whereby the titlecompound (10.7 g, 62%) was obtained.

[2868]¹H-NMR (CDCl₃) δ: 2.30-2.70 (8H, m), 3.11 (1H, br s), 3.40-3.80(4H, m), 3.60 (3H, s), 7.20-7.40 (10H, m).

[2869] MS (FAB) m/z: 339 (M+H)⁺.

Referential Example 1101-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-methoxycarbonylmethylpiperazine

[2870] In acetic acid (40 ml),1,4-dibenzyl-2-methoxycarbonylmethylpiperazine (2.04 g) was dissolved,followed by the addition of 10% palladium carbon (water content: about50%, 2.00 g). The resulting mixture was subjected to catalytic reductionat room temperature for 4 hours under 4 atmospheric pressure. Afterremoval of the catalyst by filtration, the residue obtained bydistilling the filtrate under reduced pressure was added withdichloromethane and a saturated aqueous solution of potassiumbicarbonate. The insoluble matter so precipitated was filtered off. Theorganic layer so separated was washed with saturated aqueous NaClsolution and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure. The residue was dissolved indichloromethane (30 ml), followed by the addition of6-chloro-2-naphthylsulfonyl chloride (782 mg). The resulting mixture wasstirred at 0° C. for 2 hours. To the reaction mixture, triethylamine(410 μl) was added, followed by stirring at 0° C. for further threehours. The residue obtained by distilling off the solvent under reducedpressure was purified by chromatography on a silica gel column(dichloromethane˜3% methanol dichloromethane), whereby the titlecompound (759 mg, 33%) was obtained.

[2871]¹H-NMR (CDCl₃) δ: 1.71 (1H, br s), 2.15-2.55 (4H, m), 2.90-3.05(2H, m), 3.15-3.25 (1H, m), 3.60-3.70 (5H, m), 7.55-7.60 (1H, m),7.75-7.80 (1H, m), 7.85-7.95 (3H, m), 8.30 (1H, s).

[2872] MS (FAB) m/z: 383 [(M+H)⁺, Cl³⁵], 385 [(M+H)⁺, Cl³⁷].

Referential Example 1114-tert-Butoxycarbonyl-1-[(3-chloro-1-propyl)sulfonyl]piperazine

[2873] Under an argon gas atmosphere, 1-tert-butoxycarbonylpiperazine(3.00 g) and triethylamine (2.24 ml) were dissolved in dichloromethane(40 ml) under ice cooling, followed by the addition of3-chloro-1-propanesulfonic acid chloride (1.96 g). The resulting mixturewas stirred for 20 minutes under ice cooling and then, at roomtemperature for 10 minutes. The reaction mixture was diluted withdichloromethane, washed with water and saturated aqueous NaCl solutionand then dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure. The residue was recrystallizedfrom a mixed solvent of ethyl acetate and hexane, whereby the titlecompound (4.36 g, 83%) was obtained.

[2874]¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.27-2.33 (2H, m), 3.08 (2H, t,J=7.3 Hz), 3.26 (4H, t, J=4.9 Hz), 3.53 (4H, t, J=4.9 Hz), 3.69 (2H, t,J=6.1 Hz).

[2875] MS (FAB) m/z: 327 (M+H)⁺

[2876] Elementary analysis for C₁₂H₂₃ClN₂O₄S

[2877] Calculated: C, 44.10; H, 7.09, Cl, 10.85; N, 8.57; S, 9.81.

[2878] Found: C, 44.18; H, 7.11; Cl, 10.69; N, 8.23; S, 9.76.

Referential Example 1124-tert-Butoxycarbonyl-1-[(3-hydroxy-1-propyl)sulfonyl]piperazine

[2879] In N,N-dimethylformamide (10 ml),4-tert-butoxycarbonyl-1-[(3-chloro-1-propyl)sulfonyl]piperazine (1.18 g)was dissolved, followed by the addition of potassium acetate (1.06 g).After stirring at room temperature for 2 hours, the reaction mixture wasstirred under heat at 100° C. for 3 hours. The reaction mixture wasdiluted with ethyl acetate, followed by the addition of water and asaturated aqueous solution of sodium bicarbonate. After stirring, theorganic layer so separated was washed with a 5% aqueous citric acidsolution, water and saturated aqueous NaCl solution. After drying overanhydrous sodium sulfate, the residue obtained by distilling off thesolvent under reduced pressure was dissolved in tetrahydrofuran (20 ml).To the resulting solution, water and lithium hydroxide monohydrate (221mg) were added, followed by stirring at room temperature for 18 hours.Ethyl acetate and saturated aqueous NaCl solution were added to thereaction mixture to separate an organic layer. From the water layer,another organic layer was extracted with ethyl acetate. The organiclayers were combined together, washed with saturated aqueous NaClsolution and dried over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure. The residue was recrystallizedfrom a mixed solvent of ethyl acetate an hexane, whereby the titlecompound (944 mg, 84%) was obtained.

[2880]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.04-2.11 (2H, m), 3.06 (2H, t,J=7.6 Hz), 3.25 (4H, t, J=4.9 Hz), 3.53 (4H, t, J=4.9 Hz), 3.80 (2H, q,J=5.4 Hz).

[2881] MS (FAB) m/z: 309 (M+H)⁺.

[2882] Elementary analysis for C₁₂H₂₄N₂O₅S

[2883] Calculated: C, 46.74; H, 7.84; N, 9.08; S, 10.40.

[2884] Found: C, 46.80; H, 7.92; N, 9.05; S, 10.59.

Referential Example 1134-tert-Butoxycarbonyl-1-[(3-methoxymethyloxy-1-propyl)sulfonyl]piperazine

[2885] In dichloromethane (60 ml),4-tert-butoxycarbonyl-1-[(3-hydroxy-1-propyl)sulfonyl]piperazine (3.00g) was dissolved. To the resulting solution, diisopropylethylamine (2.72ml) was added, followed by the addition of methoxymethyl chloride (1.11ml) under ice cooling. After stirring at room temperature for 15 hours,the reaction mixture was diluted with dichloromethane, washed withwater, 5% aqueous citric acid solution and saturated aqueous NaClsolution and then dried over anhydrous sodium sulfate. The solvent wasthen distilled off under reduced pressure. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=2:1),whereby the title compound (3.32 g, 97%) was obtained.

[2886]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.06-2.13 (2H, m), 3.03 (2H, m),3.25 (4H, t, J=4.9 Hz), 3.36 (3H, s), 3.52 (4H, t, J=4.9 Hz), 3.63 (2H,t, J=5.4 Hz), 4.61 (2H, s).

[2887] MS (FAB) m/z: 353 (M+H)⁺.

[2888] Elementary analysis for C₁₄H₂₈N₂O₆S

[2889] Calculated: C, 47.71; H, 8.01; N, 7.95; S, 9.10.

[2890] Found: C, 47.77; H, 8.18; N, 7.97; S, 9.16.

Referential Example 1144-tert-Butoxycarbonyl-1-[(E)-4-chloro-β-[2-(methoxymethyloxy)ethyl]-β-styrylsulfonyl]piperazineand4-tert-butoxycarbonyl-1-[(Z)-4-chloro-β-[2-(methoxymethyloxy)ethyl]-β-styrylsulfonyl]piperazine

[2891] Under an argon gas atmosphere,4-tert-butoxycarbonyl-1-[(3-methoxymethyloxy-1-propyl)sulfonyl]piperazine(800 mg) was dissolved in tetrahydrofuran (10 ml), followed by thedropwise addition of tert-butyl lithium (a 1.7M hexane solution, 1.47ml) at −78° C. The resulting mixture was stirred at −78° C. for onehour. After the addition of trimethylsilyl chloride (0.317 ml) andstirring at −78° C. for 90 minutes, tert-butyl lithium (a 1.7M hexanesolution, 1.47 ml) was added dropwise to the reaction mixture andstirring was effected at −78° C. for 90 minutes. At −78° C., a solutionof p-chlorobenzaidehyde (352 mg) in tetrahydrofuran (tetrahydrofuran: 8ml) was added dropwise to the reaction mixture. After stirring for 2hours, the temperature of the reaction mixture was allowed to rise backto room temperature over 15 hours, at which temperature it was stirredfor 6 hours. Under ice cooling, a 5% citric acid solution (20 ml) andethyl acetate (150 ml) were added to the reaction mixture. The organiclayer so separated was washed with water and saturated aqueous NaClsolution and then dried over anhydrous magnesium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (hexane:ethylacetate=3:1˜2:1), whereby the title compound was obtained as an E-form(307 mg, 28%) and Z-form (751 mg, 70%).

[2892] E-Form:

[2893]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.87 (2H, t, J=7.3 Hz), 3.21-3.28(4H, m), 3.35 (3H, s), 3.46-3.56 (4H, m), 3.80 (2H, t, J=7.3 Hz), 4.60(2H, s), 7.40 (2H, d, J=8.5 Hz), 7.46 (2H, d, J=8.5 Hz), 7.54 (1H, s).

[2894] Z-Form:

[2895]¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.77 (2H, dt, J=6.4, 1.0 Hz),2.91-2.98 (4H, m), 3.19-3.25 (4H, m), 3.38 (3H, s), 3.82 (2H, t, J=6.4Hz), 4.66 (2H, s), 7.07 (1H, s), 7.32 (2H, d, J=8.6 Hz), 7.35 (2H, d,J=8.6 Hz).

Referential Example 115 6-Chloro-1-phenylsulfonylindole

[2896] At −78° C., n-butyl lithium (a 1.61M hexane solution, 3.34 ml)was added to a solution of 6-chloroindole (777 mg) in tetrahydrofuran(25 ml), followed by heating to −40° C. over 1 hour. The reactionmixture was cooled back to −78° C. and added with benzenesulfonylchloride (867 μl). The resulting mixture was heated to room temperatureover 3 hours. Water was added to the reaction mixture, followed byextraction with dichloromethane. The organic layers were combined, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column (40 gof silica gel, hexane:ethyl acetate=5:7). The white solid so obtainedwas recrystallized from ethanol, whereby the title compound (826 mg,55%) was obtained as a white solid.

[2897]¹H-NMR (CDCl₃) δ: 6.64 (1H, d, J=3.9 Hz), 7.21 (1H, dd, J=8.3, 1.2Hz), 7.42-7.60 (5H, m), 7.88 (2H, d, J=7.3 Hz), 8.03 (1H, s).

[2898] Elementary analysis for C₁₄H₁₀ClNO₂S

[2899] Calculated: C, 57.63; H, 3.45; Cl, 12.15; N, 4.80; S, 10.99.

[2900] Found: C, 57.48; H, 3.75; Cl, 12.34; N, 4.87; S, 10.87.

[2901] In the same manner as in Referential Example 115, the compoundswhich will described below in Referential Examples 116 and 117 weresynthesized.

Referential Example 116 5-Chloro-1-phenylsulfonylindole

[2902]¹H-NMR (CDCl₃) δ: 6.61 (1H, d, J=3.9 Hz), 7.26 (1H, dd, J=8.3, 2.0Hz), 7.45 (2H, t, J=7.3 Hz), 7.50 (1H, d, J=2.0 Hz), 7.56 (1H, m), 7.59(1H, d, J=3.9 Hz), 7.86 (2H, m), 7.92 (1H, d, J=8.3 Hz).

[2903] Elementary analysis for C₁₄H₁₀ClNO₂S

[2904] Calculated: C, 57.63; H, 3.45; Cl, 12.15; N, 4.80; S, 10.99.

[2905] Found: C, 57.82; H, 3.58; Cl, 11.91; N, 4.79; S, 10.92.

Referential Example 117 5-Bromo-1-phenylsulfonylindole

[2906]¹H-NMR (CDCl₃) δ: 6.60 (1H, d, J=3.7 Hz), 7.42 (1H, dd, J=8.8, 2.0Hz), 7.45 (2H, t, J=8.8 Hz), 7.55 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=3.7Hz), 7.73 (1H, d, J=2.0 Hz), 7.86 (2H, d, J=8.8 Hz), 7.87 (1H, d, J=1H,d, J=8.8 Hz).

[2907] Elementary analysis for C₁₄H₁₀BrNO₂S

[2908] Calculated: C, 50.01; H, 3.00; N, 4.17; Br, 23.77; S, 9.54.

[2909] Found: C, 49.96; H, 2.97; N, 4.02; Br, 23.90; S, 9.53.

Referential Example 118 1-Phenylsulfonyl-5-trimethylsilylethynylindole

[2910] In tetrahydrofuran (7.00 ml), 5-bromo-1-phenylsulfonylindole(1.50 g) and triphenylphosphine (351 mg) were dissolved. Triethylamine(20 ml), N,N-dimethylformamide (7.00 ml), trimethylsilylacetylene (945μl) and palladium acetate (100 mg) were added to the resulting solutionat room temperature, followed by heating under reflux for 5 hours. Afterthe reaction mixture was allowed to cool down to room temperature, ethylacetate and water were added to the reaction mixture to separate theorganic layer. The resulting organic layer was dried over anhydroussodium sulfate and then distilled under reduced pressure to remove thesolvent. The residue was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=20:1 to 10:1), whereby the title compound(935 mg, 59%) was obtained as a white solid.

[2911]¹H-NMR (CDCl₃) δ: 0.24 (9H, s), 6.62 (1H, d, J=3.9 Hz), 7.42 (1H,dd, J=8.8, 1.5 Hz), 7.44 (2H, t, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.56(1H, d, J=3.9 Hz), 7.66 (1H, d, J=1.5 Hz), 7.85 (2H, d, J=7.8 Hz), 7.92(1H, d, J=8.8 Hz).

[2912] MS (FAB) m/z: 354 (M+H)+

Referential Example 119 5-Chloro-1-ethylindole

[2913] In benzene (10 ml), 5-chloroindole (1.52 g) was dissolved,followed by the addition of a 50% aqueous solution of sodium hydroxide(10 ml), tetrabutylammonium bromide (161 mg) and bromoethane (1.64 g).The resulting mixture was stirred at room temperature for 40 hours.After the addition of a saturated aqueous solution of ammonium chlorideto the reaction mixture, water and dichloromethane were added toseparate the organic layer. After the organic layer was dried overanhydrous sodium sulfate, the residue obtained by distilling off thesolvent under reduced pressure was purified by chromatography on asilica gel column (ethyl acetate:hexane=1:20), whereby the titlecompound (1.68 g, 93%) was obtained as colorless crystals.

[2914]¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J=7.3 Hz), 4.16 (2H, q, J=7.3 Hz),6.43 (1H, d, J=2.4 Hz), 7.14 (1H, d, J=2.4 Hz), 7.15 (1H, d, J=8.3 Hz),7.26 (1H, J=8.3 Hz), 7.59 (1H, s).

[2915] MS (EI) m/z: 179 (M+, Cl³⁵), 181 (M+, Cl³⁷).

Referential Example 120 6-Chloro-1-phenylsulfonylindole2-sulfonylChloride

[2916] After the dropwise addition of tert-butyl lithium (a 1.56Mpentane solution, 1.78 ml) to a solution of6-chloro-1-phenylsulfonylindole (777 mg) in ether (12 ml) at −78° C.,the mixture was heated to 0° C. over 30 minutes. The reaction mixturewas stirred for 1 hour and then cooled back to 78° C. Sulfurdioxide wasthen introduced into the reaction mixture. After heating to roomtemperature over 1 hour, stirring was conducted for 1 hour. The reactionmixture was concentrated under reduced pressure. Hexane was added to theconcentrate, followed by concentration under reduced pressure again. Theresidue was dissolved in dichloromethane. To the resulting solution,N-chlorosuccinimide (390 mg) was added at 0° C., followed by heatingover 1 hour to room temperature. Stirring was then conducted for 30minutes. Dichloromethane and water were added to the reaction mixture toseparate the organic layer. The resulting organic layer was dried overanhydrous sodium sulfate and then distilled under reduced pressure toremove the solvent. The residue was recrystallized from methanol,whereby the title compound (857 mg, 79%) was obtained as a white solid.

[2917]¹H-NMR (CDCl₃) δ: 7.39 (1H, dd, J=8.3, 1.6 Hz), 7.48-7.67 (4H, m),7.68 (1H, s), 8.08 (2H, d, J=7.3 Hz), 8.35 (1H, s).

[2918] Elementary analysis for C₁₄H₉ClNO₄S₂

[2919] Calculated: C, 43.09; H, 2.32; Cl, 18.17; N, 3.59; S, 16.43.

[2920] Found: C, 43.32; H, 2.67; Cl, 18.25; N, 3.64; S, 16.22.

[2921] In the same manner as in Referential Example 120, compounds whichwill be described below in Referential Examples 121 to 128 weresynthesized.

Referential Example 121 1-Phenylsulfonylindole-2-sulfonyl Chloride

[2922]¹H-NMR (CDCl₃) δ: 7.40 (1H, t, J=7.6 Hz), 7.45-7.53 (2H, m),7.57-7.67 (2H, m), 7.69 (1H, d, J=7.8 Hz), 7.73 (1H, s), 8.08 (2H, d,J=7.3 Hz), 8.31 (1H, d, J=8.8 Hz).

[2923] MS (EI) m/z: 355M+.

[2924] Elementary analysis for C₁₄H₁₀ClNO₄S₂

[2925] Calculated: C, 47.26; H, 2.83; Cl, 9.96; N, 3.94; S, 18.02.

[2926] Found: C, 47.33; H, 3.08; Cl, 10.04; N, 3.98; S, 18.18.

Referential Example 122 5-Chloro-1-phenylsulfonylindole2-sulfonylChloride

[2927]¹H-NMR (CDCl₃) δ: 7.46-7.54 (2H, m), 7.58 (1H, dd, J=9.3, 2.0 Hz),7.63 (1H, t, J=7.3 Hz), 7.64 (1H, s), 7.67 (1H, d, J=2.0 Hz), 8.06 (2H,d, J=7.3 Hz), 8.26 (1H, d, J=9.3 Hz).

[2928] MS (EI) m/z: 291 (M+, Cl³⁵), 293 (M+, Cl³⁷)

[2929] Elementary analysis for C₁₄H₉Cl₂NO₄S₂

[2930] Calculated: C, 43.09; H, 2.32; Cl, 18.27; N, 3.59; S, 16.43.

[2931] Found: C, 42.98; H, 2.51; Cl, 18.36; N, 3.59 S, 16.47.

Referential Example 123 5-Chloro-1-ethylindole-2-sulfonyl chloride

[2932]¹H-NMR (CDCl₃) δ: 1.52 (3H, t, J=7.3 Hz), 4.59 (2H, q, J=7.3 Hz),7.36 (1H, s), 7.39 (1H, d, J=8.8 Hz), 7.45 (1H, dd, J=8.8, 2.0 Hz), 7.73(1H, d, J=2.0 Hz)

[2933] MS (EI) m/z: 277 [M+, Cl³⁵], 279 [M+, Cl³⁷].

Referential Example 1241-Phenylsulfonyl-5-trimethylsilylethynylindole-2-sulfonyl chloride

[2934]¹H-NMR (CDCl₃) δ: 0.26 (9H, s), 7.48 (2H, t, J=7.8 Hz), 6.61 (1H,t, J=7.8 Hz), 7.65 (1H, s), 7.69 (1H, dd, J=8.8, 1.5 Hz), 7.79 (1H, d,J=1.5 Hz), 8.04 (2H, d, J=7.8 Hz), 8.24 (1H, d, J=8.8 Hz).

[2935] MS (FAB) m/z: 452 [(M+H)⁺, Cl³⁵], 454 [(M+H)⁺, Cl³⁷].

Referential Example 125 5-Chlorobenzo[b]furan-2-sulfonyl chloride

[2936]¹H-NMR (CDCl₃) δ: 7.57 (1H, dd, J=8.8, 2.0 Hz), 7.59 (1H, s), 7.61(1H, d, J=8.8 Hz), 7.76 (1H, d, J=2.0 Hz).

[2937] MS (EI) m/z: 250 (M+, Cl³⁵), 252 (M⁺, Cl³⁷).

[2938] Elementary analysis for C₈H₄Cl₂O₃S

[2939] Calculated: C, 38.27; H, 1.61; Cl, 28.24; S, 12.77.

[2940] Found: C, 38.33; H, 1.71; Cl, 28.16; S, 12.57.

Referential Example 126 6-Chlorobenzo[b]furan-2-sulfonyl Chloride

[2941]¹H-NMR (CDCl₃) δ: 7.43 (1H, dd, J=8.8, 2.0 Hz), 7.62 (1H, s), 7.69(1H, s), 7.70 (1H, d, J=8.8 Hz).

[2942] MS (EI) m/z: 250 (M+, Cl³⁵), 252 (M+, Cl³⁷).

[2943] Elementary analysis for C₈H₄Cl₂O₃S

[2944] Calculated: C, 38.27; H, 1.61; Cl, 28.24; S, 12.77.

[2945] Found: C, 38.31; H, 1.60; Cl, 28.34; S, 12.60.

Referential Example 127 5-Chlorobenzo[b]thiophene-2-sulfonyl Chloride

[2946]¹H-NMR (CDCl₃) δ: 7.57 (1H, dd, J=8.8, 2.0 Hz), 7.85 (1H, d, J=8.8Hz), 7.96 (1H, d, J=2.0 Hz), 8.08 (1H, s).

[2947] MS (FD) m/z: 266 (M+, Cl³⁵), 268 (M+, Cl³⁷).

Referential Example 128 6-Chlorobenzo[b]thiophene-2-sulfonyl Chloride

[2948]¹H-NMR (CDCl₃) δ: 7.51 (1H, dd, J=8.3, 1.5 Hz), 7.90 (1H, d, J=8.3Hz), 7.92 (1H, s), 8.11 (1H, s).

[2949] MS (FAB) m/z: 266 [(M+H)⁺, Cl³⁵], 268 [(M+H)⁺, Cl³⁷)].

Referential Example 1291-tert-Butoxycarbonyl-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]piperazine

[2950] To a solution of 5-chloro-1-phenylsulfonylindole-2-sulfonylchloride (4.41 g) in dichloromethane (75 ml), tert-butyl-1-piperazinecarboxylate (2.21 g) and triethylamine (1.65 ml) were added under icecooling. The resulting mixture was stirred at room temperature for 3hours. After completion of the reaction, water and dichloromethane wereadded to the reaction mixture. The organic layer so separated was driedover anhydrous sodium sulfate and then distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (ethyl acetate:n-hexane=1:20), whereby the titlecompound (3.63 g, 60%) was obtained as colorless crystals.

[2951]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.35-3.42 (4H, br), 3.50-3.55 (4H,br), 7.40-7.48 (4H, m), 7.53-7.58 (2H, m), 8.00-8.05 (2H, m), 8.23 (1H,d, J=8.8 Hz).

[2952] In the same manner as in Referential Example 129, compounds whichwill described below in Referential Examples 130 to 133 weresynthesized.

Referential Example 1301-tert-Butoxycarbonyl-4-[(1-phenylsulfonylindol-2-yl)sulfonyl]piperazine

[2953]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.34-3.44 (4H, br), 3.48-3.56 (4H,br), 7.33 (1H, t, J=7.3 Hz), 7.36-7.45 (2H, m), 7.47-7.61 (4H, m), 8.04(2H, d, J=7.3 Hz), 8.29 (1H, d, J=8.8 Hz).

[2954] MS (EI) m/z: 505M+.

Referential Example 1311-tert-Butoxycarbonyl-4-[(5-chloro-1-ethylindol-2-yl)sulfonyl]piperazine

[2955]¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.3 Hz), 1.43 (9H, s), 3.16-3.23(4H, m), 3.48-3.55 (4H, m), 4.45 (2H, q, J=7.3 Hz), 7.03 (1H, s),7.32-7.34 (2H, m), 7.66 (1H, d, J=2.0 Hz).

[2956] MS (EI) m/z: 427 (M+, Cl³⁵), 429 (M+, Cl³⁷).

Referential Example 1321-tert-Butoxycarbonyl-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]homopiperazine

[2957]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.98-2.17 (2H, m), 3.42-3.57 (8H,m), 7.28 (1H, s), 7.41-7.46 (3H, m), 7.53-7.57 (2H, m), 8.05 (2H, d,J=7.3 Hz), 8.20 (1H, d, J=9.3 Hz).

[2958] MS (FAB) m/z: 554 [(M+H)⁺, Cl³⁵], 556 [(M+H)⁺, Cl³⁷].

Referential Example 133cis-1-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3,5-dimethylpiperazine

[2959]¹H-NMR (CDCl₃) δ: 1.07 (6H, d, J=6.4 Hz), 2.45-2.55 (2H, m),2.95-3.05 (2H, m); 3.75-3.80 (2H, m), 7.35-7.50 (4H, m), 7.50-7.60 (2H,m), 8.00-8.05 (2H, m), 8.22 (1H, d, J=9.3 Hz).

[2960] MS (FAB) m/z: 468 [(M+H)⁺, Cl³⁵], 470 [(M+H)⁺, Cl³⁷].

Referential Example 1341-[(5-Chloro-lphenylsulfonylindol-2-yl)sulfonyl]-3-(ethoxycarbonyl)piperazine

[2961] A saturated solution of hydrochloride in ethanol was added totert-butyl 1-(3-ethoxycarbonyl)piperazinecarboxylate (3.97 g) and themixture was stirred for 30 minutes. After the solvent was distilled offunder reduced pressure, the residue was suspended in dichloromethane(200 ml). To the resulting suspension,5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (6.00 g) andtriethylamine (6.40 ml) were added, followed by stirring at roomtemperature for 3 hours. Water and dichloromethane were added to thereaction mixture. The organic layer so separated was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (methanol:dichloromethane=1:20), whereby the title compound (4.44g, 56%) was obtained as colorless crystals.

[2962]¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=6.8 Hz), 2.87-2.95 (1H, m),3.11-3.28 (3H, m), 3.57-3.66 (2H, m), 3.91-3.98 (1H, m), 4.17 (2H, q,J=6.8 Hz), 7.38-7.48 (4H, m), 7.55-7.59 (2H, m), 8.03 (2H, d, J=7.8 Hz),8.21 (1H, d, J=9.3 Hz).

[2963] MS (EI) m/z: 511 (M+, Cl³⁵), 513 (M+, Cl³⁷)⁺.

Referential Example 1351-tert-Butoxycarbonyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[2964] To1-tert-butoxycarbonyl-4-[(5-chloro-lphenylsulfonylindol-2-yl)sulfonyl]piperazine(4.84 g), a 0.5N methanol solution of sodium hydroxide (20 ml) wasadded, followed by stirring at room temperature for 1 hour. Under icecooling, a saturated aqueous solution of ammonium chloride was added tothe reaction mixture. Water and dichloromethane were then added toseparate the organic layer. The organic layer was dried over anhydroussodium sulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(methanol:dichloromethane=1:20), whereby the title compound (3.33 g,93%) was obtained as colorless powder.

[2965]¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 3.05-3.14 (4H, m), 3.48-3.57 (4H,m), 6.96 (1H, d, J=2.0 Hz), 7.33 (1H, dd, J=8.8, 2.0 Hz), 7.38 (1H, d,J=8.8 Hz), 7.67 (1H, d, J=2.0 Hz), 8.78 (1H, br).

[2966] MS (FAB) m/z: 400 [(M+H)⁺, Cl³⁵], 402 [(M+H)⁺, Cl³⁷].

[2967] In the same manner as in Referential Example 135, the compoundshown in Referential Example 136 was synthesized.

Referential Example 1361-[(5-Chloroindol-2-yl)sulfonyl]-3-methoxycarbonylpiperazine

[2968] In the same manner as in Referential Example 135, the titlecompound was obtained.

[2969]¹H-NMR (CDCl₃) δ: 2.70-2.82 (1H, m), 2.84-2.97 (2H, m), 3.06-3.16(1H, m), 3.37-3.46 (1H, m), 3.61 (1H, dd, J=8.3, 3.4 Hz), 3.69-3.80 (1H,m), 3.75 (3H, s), 6.98 (1H, s), 7.32 (1H, dd, J=8.8, 2.0 Hz), 7.38 (1H,d, J=8.8 Hz), 7.67 (1H, s), 8.80 (1H, s).

[2970] MS (EI) m/z: 357 (M+, Cl³⁵), 359 (M+, Cl³⁷)⁺.

Referential Example 1373-(N-Methylcarbamoyl)-1-[(5-chloroindol-2-yl)sulfonyl]piperazine

[2971] In tetrahydrofuran (25 ml),1-[(5-chloroindol-2-yl)sulfonyl]-3-methoxycarbonylpiperazine (480 mg)was dissolved. After a 0.2N methanol solution (7 ml) of sodium hydroxideand water (2 ml) were added to the resulting solution and the mixturewas stirred at room temperature for 1 hour, the solvent was distilledoff under reduced pressure. The resulting yellow amorphous substance(520 mg) was dissolved in N,N-dimethylformamide (60 ml). At roomtemperature, 1-hydroxybenzotriazole (18.1 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (334 mg),methylamine hydrochloride (90.5 mg) and N-methylmorpholine (271 mg) wereadded to the resulting solution, followed by stirring at roomtemperature for 12 hours. The solvent was then distilled off underreduced pressure. Water and ethyl acetate were added to the residue toseparate the organic layer. The organic layer was dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue was purified by chromatography on a silica gelcolumn (methanol:dichloromethane=1:50), whereby the title compound (140mg, 29%) was obtained as a brown amorphous solid.

[2972]¹H-NMR (DMSO-d₆) δ: 2.39-2.52 (2H, m), 2.64 (3H, d, J=3.9 Hz),2.18-2.30 (1H, m), 2.94-3.00 (1H, m), 3.20-3.37 (2H, m), 3.57-3.66 (1H,m), 6.90-6.95 (1H, br), 7.22-7.27 (1H, br), 7.44-7.49 (1H, m), 7.66-7.78(2H, m), 8.04-8.17 (3H, m), 12.24 (1H, m).

Referential Example 138 1-[(5-Chloroindol-2-yl)sulfonyl]piperazinehydrochloride

[2973] In methanol (100 ml),1-tert-butoxycarbonyl-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]piperazine (3.63 g) was dissolved. Under ice cooling, a 0.2Nmethanol solution of sodium hydroxide (100 ml) was added to theresulting solution, followed by stirring at room temperature for 12hours. After a saturated aqueous solution of ammonium chloride was addedto the reaction mixture under ice cooling, water and dichloromethanewere added to separate the organic layer. The organic layer was driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. After the solid so precipitated was collected byfiltration, it was dissolved in saturated ethanol hydrochloride,followed by stirring for 30 minutes. The reaction mixture was distilledunder reduced pressure to remove the solvent, followed by drying underreduced pressure, whereby the title compound (1.25 g, 54%) was obtainedas colorless powder.

[2974]¹H-NMR (DMSO-d₆) δ: 3.25-3.43 (8H, br), 7.46 (1H, d, J=8.8 Hz),7.64 (1H, d, J=8.8 Hz), 7.93 (1H, s), 9.33 (1H, br), 12.70 (1H, br).

[2975] MS (EI) m/z: 298 (M+, Cl³⁵), 300 (M+, Cl³⁷).

[2976] Elementary analysis for C₁₂H₁₄ClN₃O₂S.HCl.0.5H₂O

[2977] Calculated: C, 41.75; H, 4.67; Cl, 20.54; N, 12.17; S, 9.29.

[2978] Found: C, 41.78; H, 4.98; Cl, 20.40; N, 11.88; S, 9.34.

Referential Example 1391-tert-Butoxycarbonyl-4-[(5-chloro-1-methylindol-2-yl)sulfonyl]piperazine

[2979] Sodium hydride (about 60% in oil, 50.3 mg) washed twice withpetroleum ether was suspended in tetrahydrofuran (10 ml), followed bythe addition of a solution of1-tert-butoxycarbonyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (457mg) in tetrahydrofuran (10 ml) under ice cooling. The resulting mixturewas stirred for 30 minutes. Under ice cooling, iodomethane (179 mg) wasadded to the reaction mixture. The resulting mixture was heated to roomtemperature and stirred for 85 hours. Water and diethyl ether were addedto separate the organic layer. The organic layer was dried overanhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent. The residue was purified by chromatography on asilica gel column (methanol:dichloromethane=1:50), whereby the titlecompound (270 mg, 57%) was obtained as colorless powder.

[2980]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 3.14-3.21 (4H, m), 3.48-3.55 (4H,m), 3.96 (3H, s), 7.06 (1H, s), 7.31 (1H, d, J=9.3 Hz), 7.36 (1H, d,J=9.3, 2.0 Hz), 7.66 (1H, d, J=2.0 Hz).

[2981] MS (FAB) m/z: 413 [(M+H)⁺, Cl³⁵], 415 [(M+H)⁺, Cl³⁷].

Referential Example 1401-tert-Butoxycarbonyl-4-[(5-chloro-1-ethoxycarbonylmethylindol-2-yl)sulfonyl]piperazine

[2982] In the same manner as in Example 139, the title compound wasobtained.

[2983]¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.3 Hz), 1.43 (9H, s), 3.10-3.19(4H, m), 3.45-3.53 (4H, m), 4.22 (2H, q, J=7.3 Hz), 5.15 (2H, s), 7.15(1H, s), 7.17 (1H, d, J=8.8 Hz), 7.26 (1H, s), 7.36 (1H, dd, J=8.8, 2.0Hz), 7.68 (1H, d, J=2.0 Hz).

[2984] MS (FAB) m/z: 485 [(M+H)⁺, Cl³⁵], 487 [(M+H)⁺, Cl³⁷].

Referential Example 141cis-1-[(4-Bromobenzoyl)-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-2,6-dimethylpiperazine

[2985] In dichloromethane (40 ml),cis-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3,5-dimethylpiperazine(1.30 g) was dissolved. To the resulting suspension,diisopropylethylamine (645 μl) was added under ice cooling, followed bythe dropwise addition of a solution of 4-bromobenzoyl chloride (0.74 g)in dichloromethane (5 ml). Stirring was then effected at roomtemperature for 3 hours. A saturated aqueous solution of sodiumbicarbonate was added to the reaction mixture. The organic layer thusseparated was washed with 0.5N hydrochloric acid and saturated aqueousNaCl solution, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=2:1 to 1:1),whereby the title compound (1.8 g, 97%) was obtained as a pale yellowamorphous.

[2986]¹H-NMR (CDCl₃) δ: 1.45 (6H, d, J=6.8 Hz), 3.05-3.15 (2H, m), 3.74(2H, m), 4.40 (2H, br), 7.23 (2H, d, J=8.8 Hz), 7.40-7.50 (4H, m),7.50-7.60 (4H, m), 8.00-8.05 (2H, m), 8.24 (1H, d, J=9.3 Hz).

[2987] MS (EI) m/z: 649 [(M+H)⁺, Cl³⁵], 651 [(M+H)⁺, Cl³⁷].

Referential Example 142 Ethyl-2-(4-pyridyl)-5-pyrimidinecarboxylic Acid

[2988] Sodium ethoxide (590 mg) was dissolved in anhydrous ethanol (50ml) at room temperature. To the resulting solution, 4-amidinopyridinehydrochloride (1.31 g) was added, followed by the dropwise addition of asolution of ethyl 2,2-diformylacetate (1.20 g) in anhydrous ethanol (50ml). The resulting mixture was heated under reflux for 6 hours. To theresidue obtained by distilling off the solvent under reduced pressure,dichloromethane and water were added. The organic layer thus separatedwas dried over anhydrous sodium sulfate. After the solvent wasconcentrated under reduced pressure, the residue was crystallized inethanol, whereby the title compound (279 mg, 15%) was obtained ascolorless crystals.

[2989]¹H-NMR (DMSO-d₆) δ: 1.46 (3H, t, J=7.3 Hz), 4.48 (2H, q, J=7.3Hz), 8.35 (2H, d, J=5.9 Hz), 8.82 (2H, d, J=5.9 Hz), 9.38 (2H, s).

[2990] MS (FAB) m/z: 230 (M+H)⁺.

[2991] Elementary analysis for C₁₂H₁₁N₃O₂

[2992] Calculated: C, 62.87; H, 4.84; N, 18.33.

[2993] Found: C, 62.80; H, 4.78; N, 18.25.

Referential Example 143 2-(4-Pyridyl)-5-pyrimidinecarboxylic Acid

[2994] In the same manner as in Referential Example 11, a reaction waseffected using the ethyl 2-(4-pyridyl)-5-pyrimidinecarboxylate insteadas a starting material, whereby the title compound was obtained.

[2995]¹H-NMR (DMSO-d₆) δ: 8.32 (2H, d, J=5.9 Hz), 8.82 (2H, d, J=5.9Hz), 9.38 (2H, s).

[2996] MS (FAB) m/z: 201 (M+H)⁺.

[2997] Elementary analysis for C₁₀H₇N₃O₂.0.1H₂O

[2998] Calculated: C, 59.17; H, 3.58; N, 20.70.

[2999] Found: C, 59.09; H, 3.49; N, 20.69.

Referential Example 1441-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[3000] In the same manner as in Referential Example 12, a reaction waseffected using 5-bromo-2-pyrimidinecarboxylic acid and1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride as startingmaterials, whereby the title compound was obtained as a colorless solid.

[3001]¹H-NMR (CDCl₃) δ: 3.14-3.17 (2H, m), 3.25-3.29 (2H, m), 3.52-3.55(2H, m), 3.92-3.95 (2H, m), 7.97 (1H, s), 7.32-7.40 (2H, m), 7.69 (1H,s), 8.79 (1H, br, s), 8.84 (2H, s).

[3002] MS (FAB) m/z: 484 [(M+H)⁺, Cl³⁵ and Br⁷⁹], 486 [(M+H)⁺, Cl³⁵ andBr⁸¹, Cl³⁷ and Br⁷⁹], 488 [(M+H)⁺, Cl³⁷ and Br⁸¹].

Referential Example 145 6-Chloro-2-mercaptobenzothiazole

[3003] Under ice cooling, a solution of p-chloroaniline (5.70 g) inacetic acid (7 ml) was added dropwise to disulfur dichloride (25.0 ml)over 30 minutes, followed by stirring at room temperature for 3 hoursand then at about 80° C. for 3 hours. Benzene (50 ml) was added to thereaction mixture. The green crystals were collected by filtration andwashed with benzene. The resulting crystals were dissolved in ice water(500 ml) and the solution was stirred for 1 hour. To the reactionmixture, a 6N aqueous solution of sodium hydroxide was added to make themixture alkaline. Sodium bicarbonate (6 g) was then added and themixture was stirred at 100° C. for 1 hour. Activated carbon was added tothe reaction mixture, followed by Celite filtration. To the filtrate,carbon disulfide (2.70 ml) was added, followed by heating to about 50°C. Stirring was then conducted for 1.5 hours. After cooling to roomtemperature, the reaction mixture was made acidic with 1N hydrochloricacid. Colorless powder thus precipitated was collected by filtration anddried, whereby the title compound (1.30 g, 14%) was obtained.

[3004]¹H-NMR (DMSO-d₆) δ: 7.28 (1H, d, J=8.3 Hz), 7.45 (1H, dd, J=8.3,2.0 Hz), 7.86 (1H, d, J=2.0 Hz).

[3005] MS (FAB) m/z: 202 [(M+H)⁺, Cl³⁵], 204 [(M+H)⁺, Cl³⁷].

[3006] Elementary analysis for C₇H₄ClNS₂

[3007] Calculated: C, 41.68; H, 2.00; Cl, 17.58; N, 6.94; S, 31.80.

[3008] Found: C, 41.64; H, 2.13; Cl, 17.83; N, 6.94; S, 31.70.

Referential Example 1461-tert-Butoxycarbonyl-4-[(5-chloroenzothiazol-2-yl)sulphenyl]piperazine

[3009] At room temperature, tert-butyl 1-piperazine carboxylate (5.58g), 5-chloro-2-mercaptobenzothiazole (1.21 g) and sodium hydroxide (0.48g) were dissolved in water (25 ml), followed by the dropwise addition ofan aqueous solution (25 ml) containing iodine (1.53 g) and potassiumiodide (1.65 g). The colorless crystals so precipitated were collectedby filtration, washed with water and dried under reduced pressure,whereby the title compound (1.1 g, 48%) was obtained.

[3010]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.24 (4H, br), 3.58 (4H, br s),7.26 (1H, m), 7.70 (1H, d, J=8.3 Hz), 7.81 (1H, s).

[3011] MS (FAB) m/z: 386 [(M+H)⁺, Cl³⁵], 388 [(M+H)⁺, Cl³⁷].

Referential Example 1471-tert-Butoxycarbonyl-4-[(6-chlorobenzothiazol-2-yl)sulphenyl]piperazine

[3012] In the same manner as in Referential Example 146, the titlecompound was obtained.

[3013]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.24 (4H, br s), 3.58 (4H, br s),7.37 (1H, dd, J=8.8, 2.0 Hz), 7.73 (1H, d, J=8.8 Hz), 7.77 (1H, d, J=2.0Hz).

[3014] MS (FAB) m/z: 386 [(M+H)⁺, Cl³⁵], 388 [(M+H)⁺, Cl³⁷].

Referential Example 1481-tert-Butoxycarbonyl-4-[(5-chlorobenzothiazol-2-yl)sulfonyl]piperazine

[3015] At room temperature,1-tert-butoxycarbonyl-4-[(5-chlorobenzothiazol-2-yl)sulphenyl]piperazine(1.10 g) and potassium carbonate (1.30 g) were suspended in a rLLixedsolvent of ethanol (30 ml) and water (10 ml), followed by the dropwiseaddition of a solution of 3-chloroperbenzoic acid (2.11 g) in ethanol(25 ml) at 0° C. The reaction mixture was heated to room temperature andstirred for 24 hours. Sodium thiosulfate and ethyl acetate were added toseparate the organic layer. The organic layer thus obtained was driedover anhydrous magnesium sulfate. The residue obtained by distilling offthe solvent was purified by chromatography on a silica gel column(dichloromethane˜2% methanol—dichloromethane), whereby the titlecompound (293 mg, 25%) was obtained.

[3016]¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 3.35-3.43 (4H, m), 3.51-3.58 (4H,m), 7.55 (1H, dd, J=8.8, 1.5 Hz), 7.90 (1H, d, J=8.8 Hz), 8.18 (1H, d,J=1.5 Hz).

[3017] MS (FAB) m/z: 418 [(M+H)⁺, Cl³⁵], 420 [(M+H)⁺, Cl³⁷]

Referential Example 1491-tert-Butoxycarbonyl-4-[(6-chlorobenzothiazol-2-yl)sulfonyl]piperazine

[3018] In the same manner as in Referential Example 148, the titlecompound was obtained.

[3019]¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 3.35-3.43 (4H, m), 3.50-3.58 (4H,m), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.97 (1H, d, J=2.0 Hz), 8.10 (1H, d,J=8.8 Hz).

[3020] MS (FAB) m/z: 418 [(M+H)⁺, Cl³⁵], 420 [(M+H)⁺, Cl³⁷].

[3021] In the same manner as in Referential Example 35, compounds shownin Referential Examples 150 and 151 were synthesized, respectively.

Referential Example 1501-[(5-Chlorobenzothiazol-2-yl)sulfonyl]piperazine hydrochloride

[3022]¹H-NMR (DMSO-d₆) δ: 3.23 (4H, br s), 3.56 (4H, br s), 7.78 (1H,dd, J=8.8, 2.0 Hz), 8.39-8.43 (2H, m).

[3023] MS (FAB) m/z: 318 [(M+H)⁺, Cl³⁵], 320 [(M+H)⁺, Cl³⁷].

Referential Example 1511-[(6-Chlorobenzothiazol-2-yl)sulfonyl]piperazine Hydrochloride

[3024]¹H-NMR (DMSO-d₆) δ: 3.21-3.27 (4H, m), 3.52-3.57 (4H, m), 7.79(1H, dd, J=8.8, 2.0 Hz), 8.28 (1H, d, J=8.8 Hz), 8.53 (1H, d, J=2.0 Hz).

[3025] MS (FAB) m/z: 318 [(M+H)⁺, Cl³⁵], 320 [(M+H)⁺, Cl³⁷].

[3026] Elementary analysis for C₁₁H₁₂ClN₃O₂S₂.1.05HCl.0.5H₂O

[3027] Calculated: C, 36.19; H, 3.88; Cl, 19.91; N, 11.51; S, 17.57.

[3028] Found: C, 36.19; H, 4.10; Cl, 20.08; N, 11.50; S, 17.19.

[3029] In the same manner as in Referential Example 1, compounds shownin Referential Examples 152 to 155 were synthesized, respectively.

Referential Example 1521-[(5-Chlorobenzo[b]furan-2-yl)sulfonyl]piperazine hydrochloride

[3030]¹H-NMR (DMSO-d₆) δ: 3.20 (4H, br), 3.45 (4H, br), 7.62 (1H, d,J=8.8 Hz), 7.76 (1H, s), 7.85 (1H, d, J=8.8 Hz), 7.96 (1H, s), 9.41 (1H,br).

[3031] MS (FAB) m/z: 301 [(M+H)⁺, Cl³⁵], 303 [(M+H)⁺, Cl³⁷].

[3032] Elementary analysis for C₁₂H₁₃ClN₂O₃S.HCl.0.1H₂O

[3033] Calculated: C, 42.51; H, 4.22; Cl, 20.91; N, 8.26; S, 9.46.

[3034] Found: C, 42.38; H, 4.33; Cl, 20.92; N, 8.18; S, 9.58.

Referential Example 1531-[(6-Chlorobenzo[b]furan-2-yl)sulfonyl]piperazine hydrochloride

[3035]¹H-NMR (DMSO-d₆) δ: 3.20 (4H, t, J=4.9 Hz), 3.42 (4H, t, J=4.9Hz), 7.51 (1H, d, J=7.8 Hz), 7.82 (1H, s), 7.89 (1H, d, J=7.8 Hz), 9.18(1H, br).

[3036] MS (FAB) m/z: 301 [(M+H)⁺, Cl³⁵], 303 [(M+H)⁺, Cl³⁷].

[3037] Elementary analysis for C₁₂H₁₃ClN₂O₃S HCl 0.5H₂O

[3038] Calculated: C, 41.63; H, 4.37; Cl, 20.48; N, 8.09; S, 9.26.

[3039] Found: C, 41.54; H, 4.32; Cl, 20.49; N, 7.90; S, 9.07.

Referential Example 1541-[(5-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazine hydrochloride

[3040]¹H-NMR (DMSO-d₆) δ: 3.20-3.50 (8H, m), 7.64 (1H, dd, J=8.8, 2.0Hz), 8.12 (1H, s), 8.20 (1H, s), 8.23 (1H, d, J=8.8 Hz), 9.22 (2H, brs).

[3041] MS (FAB) m/z: 317 [(M+H)⁺, Cl³⁵], 319 [(M+H)⁺, Cl³⁷].

[3042] Elementary analysis for C₁₂H₁₃ClN₂O₂S₂.HCl.1.6H₂O

[3043] Calculated: C, 37.72; H, 4.54; Cl, 18.56; N, 7.33; S, 16.78.

[3044] Found: C, 37.56; H, 4.67; Cl, 18.72; N, 7.17; S, 16.56.

Referential Example 1551-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazine Hydrochloride

[3045]¹H-NMR (DMSO-d₆) δ: 3.20-3.38 (8H, m), 7.59 (1H, dd, J=8.8, 2.0Hz), 8.10 (1H, d, J=8.8 Hz), 8.16 (1H, s), 8.36 (1H, d, J=8.8 Hz), 9.29(2H, br s).

[3046] MS (FAB) m/z: 317 [(M+H)⁺, Cl³⁵], 319 [(M+H)⁺, Cl³⁷].

[3047] Elementary analysis for C₁₂H₁₃ClN₂O₂S₂ HCl

[3048] Calculated: C, 40.80; H, 3.99; Cl, 20.07; N, 7.93; S, 18.15.

[3049] Found: C, 40.64; H, 4.04; Cl, 20.06; N, 7.90; S, 17.91.

Referential Example 1561-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3050] In the same manner as in Referential Example 12, the titlecompound was obtained.

[3051]¹H-NMR (CDCl₃) δ: 3.10-3.13 (2H, m), 3.22-3.25 (2H, m), 3.49-3.53(2H, m), 3.90-3.94 (2H, m), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd,J=8.8, 1.5 Hz), 7.91-7.95 (3H, m), 8.30 (1H, br s), 8.82 (2H, s).

[3052] MS (FAB) m/z: 495 [(M+H)⁺, Cl³⁵ and Br⁷⁹], 497 [(M+H)⁺, Cl³⁵ andBr⁸¹, Cl³⁷ and Br⁷⁹], 499 [(M+H)⁺, Cl³⁷ and Br⁸¹].

Referential Example 1571-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(6-chlorobenzothien-2-yl)sulfonyl]piperazine

[3053]¹H-NMR (CDCl₃) δ: 3.19-3.23 (2H, m), 3.29-3.33 (2H, m), 3.53-3.56(2H, m), 3.93-3.97 (2H, m), 7.46 (1H, dd, J=8.8, 1.5 Hz), 7.77 (1H, s),7.83 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=1.5 Hz), 8.84 (2H, s).

[3054] MS (FAB) m/z: 501 [(M+H)⁺, Cl³⁵ and Br⁷⁹], 503 [(M+H)⁺, Cl³⁵ andBr⁸¹, Cl³⁷ and Br⁷⁹], 505 [(M+H)⁺, Cl³⁷ and Br⁸¹].

[3055] Elementary analysis for C₁₇H₁₄BrClN₄O₃S₂

[3056] Calculated: C, 40.69; H, 2.81; N, 11.17; S, 12.78.

[3057] Found: C, 40.90; H, 2.87; N, 10.92; S, 12.87.

Referential Example 158 1-Benzyl-4-tert-butoxycarbonylpiperazine

[3058] In acetonitrile (80 ml), tert-butyl 1-piperazine carboxylate(2.50 g) was dissolved. Under ice cooling, benzyl bromide (1.59 ml) andtriethylamine (1.87 ml) were added dropwise to the resulting solution,followed by stirring at room temperature for 90 minutes. After thesolvent was distilled off under reduced pressure, distilled water anddichloromethane were added to the residue to separate the organic layer.The organic layer was washed with saturated aqueous NaCl solution anddried over anhydrous sodium sulfate. The residue obtained by distillingoff the solvent under reduced pressure was purified by chromatography ona silica gel column (ethyl acetate:hexane=1:20 to 1:5), whereby thetitle compound (3.12 g, 84%) was obtained as colorless powder.

[3059]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.38 (4H, t, J=4.9 Hz), 3.42 (4H,t, J=4.8 Hz), 3.51 (2H, s), 7.25-7.29 (1H, m), 7.30-7.33 (4H, m).

[3060] MS (EI) m/z: 276M+.

Referential Example 159 1-Benzylpiperazine Hydrochloride

[3061] To 1-benzyl-4-tert-butoxycarbonylpiperazine (3.12 g), saturatedethanol hydrochloride was added, followed by stirring for 90 minutes atroom temperature. The solvent was distilled off under reduced pressure,followed by drying, whereby the title compound (2.73 g, 97%) wasobtained as white powder.

[3062]¹H-NMR (DMSO-d₆) δ: 3.05-3.67 (9H, m), 4.38 (2H, br), 7.35-7.70(5H, m), 9.61 (1H, br).

[3063] MS (EI) m/z: 176M+.

[3064] Elementary analysis for C₁₁H₁₆N₂.2HCl.0.2H₂O

[3065] Calculated: C, 52.27; H, 7.34; Cl, 28.05; N, 11.27.

[3066] Found: C, 52.04; H, 7.36; Cl, 27.89; N, 11.24.

Referential Example 160 1-Benzyl-4-sulfamoylpiperazine

[3067] Chlorosulfonyl isocyanate (0.35 ml) was dissolved indichloromethane (5 ml). Under ice cooling, tert-butanol (0.21 ml) wasadded dropwise to the resulting solution, followed by stirring for 30minutes. After the reaction mixture was added dropwise to a solution of1benzylpiperazine dihydrochloride (0.25 g) in dichloromethane (20 ml)under ice cooling, triethylamine (0.28 ml) was added. The mixture wasstirred for 30 minutes under ice cooling and then at room temperaturefor 1 hour. Distilled water and dichloromethane were added to separatethe organic layer. The organic layer was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column(methanol:dichloromethane=1:50 to 1:25), whereby1-benzyl-[4-(N-tert-butoxycarbonyl)sulfamoyl]piperazine was obtained ascolorless powder. To the resulting powder, saturated solution ofhydrochloride in ethanol was added and the mixture was stirred at roomtemperature for 1 hour. After the solvent was distilled off underreduced pressure, a saturated aqueous solution of sodium bicarbonate anddichloromethane were added to the residue to separate the organic layer.The resulting organic layer was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent, whereby thetitle compound (0.26 g, quant.) was obtained as colorless powder.

[3068]¹H-NMR (CDCl₃) δ: 2.58 (4H, t, J=4.9 Hz), 3.22 (4H, t, J=4.9 Hz),3.56 (2H, s), 4.33 (2H, br), 7.27-7.36 (5H, m).

[3069] MS (EI) m/z: 255M+.

Referential Example 161 3,4-Bis(bromomethyl)-1-chlorobenzene

[3070] In acetonitrile (500 ml), 1-chloro-3,4-dimethylbenzene (20.0 ml)was dissolved and to the resulting solution, N-bromosuccinimide (53.0 g)and azoisobutyronitrile (1.20 g) were added, followed by heating underreflux for 1 hour. After cooling, the solvent was distilled off underreduced pressure and dichloromethane was then added to the residue. Fromthe resulting mixture, the precipitate was filtered off. The filtratewas concentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column (hexane), whereby the titlecompound (41.5 g, 93%) was obtained as a colorless oil.

[3071]¹H-NMR (CDCl₃) δ: 4.59 (2H, s), 4.61 (2H, s), 7.27-7.36 (3H, m).

[3072] MS (EI) m/z: 295M⁺.

Referential Example 1621-Benzyl-4-[(5-chloroisoindol-2-yl)sulfonyl]piperazine

[3073] In ethanol (5 ml), 1-benzyl-4-sulfamoylpiperazine (251 mg) wasdissolved. To the resulting solution,3,4-bis(bromomethyl)-1-chlorobenzene (293 mg) and potassium carbonate(204 mg) were added, followed by heating under reflux for 3.5 hours.After cooling, the precipitate was filtered off. The filtrate was thendistilled under reduced pressure and the residue was purified bychromatography on a silica gel column(dichloromethane˜ethanol:dichloromethane=1:100), whereby the titlecompound (222 mg, 58%) was obtained.

[3074]¹H-NMR (CDCl₃) δ: 2.37-2.58 (4H, m), 3.24-3.41 (4H, m), 3.53 (2H,s), 4.64 (4H, m), 7.13-7.34 (8H, m).

[3075] MS (FAB) m/z: 392 [(M+H)⁺, Cl³⁵], 394 [(M+H), Cl³⁷].

Referential Example 163 1-[(5-Chloroisoindol-2-yl)sulfonyl]piperazine

[3076] To a solution of1-benzyl-4-[(5-chloroisoindol-2-yl)sulfonyl]piperazine (222 mg) in1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (81 mg) wasadded under ice cooling. The resulting mixture was stirred for 15minutes and then heated under reflux for 1 hour. After cooling,anhydrous methanol was added to the residue obtained by distilling offthe solvent under reduced pressure. The mixture was heated under refluxfor 11 hours. After cooling, the-residue obtained by distilling off thesolvent under reduced pressure was purified by chromatography on asilica gel column (ethanol:dichloromethane=1:50 to 1:10), whereby thetitle compound (120 mg, 70%) was obtained.

[3077]¹H-NMR (CDCl₃) δ: 2.96 (4H, t, J=4.4 Hz), 3.09-3.22 (1H, br), 3.30(4H, t, J=4.4 Hz), 4.65 (4H, m), 7.14-7.35 (3H, m).

[3078] MS (FAB) m/z: 302 [(M+H)⁺, Cl³⁵], 304 [(M+H)⁺, Cl³⁷].

Referential Example 1641-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroisoindol-2-yl)sulfonyl]piperazine

[3079] In the same manner as in Referential Example 12, the titlecompound was obtained.

[3080]¹H-NMR (CDCl₃) δ: 3.35 (2H, t, J=4.9 Hz), 3.44 (2H, t, J=4.9 Hz),3.49 (2H, t, J=4.9 Hz), 3.91 (2H, t, J=4.9 Hz), 4.65-4.68 (4H, m), 7.17(1H, d, J=8.3 Hz), 7.23 (1H, s), 7.28 (1H, m), 8.88 (2H, s).

[3081] MS (EI) m/z: 486M⁺.

Referential Example 165 2-(Furan-2-yl)-5-(pyridin-4-yl)pyrazine

[3082] At room temperature, 2-chloro-5-(furan-2-yl)pyrazine (N. Sato, J.Heterocyclic Chem., 19, 407(1982)) (1.00 g) and (pyridin-4-yl)boronicacid (1.09 g) were suspended in a mixed solvent of dimethoxyethane (50ml) and methanol (50 ml), followed by the successive addition oftetrakis(triphenylphosphine)palladium (O) (640 mg) and cesium fluoride(5.55 g). The resulting mixture was heated under reflux for 16 hours.After cooling, the reaction mixture was concentrated. Dichloromethaneand water were added to the concentrate to separate the organic layer.The organic layer was dried over anhydrous sodium sulfate, treated withactivated carbon and filtered through Celite. After the filtrate wasconcentrated to about 5 ml, petroleum ether (50 ml) was added to theconcentrate. Yellow crystalline powder thus precipitated was collectedby filtration and dried, whereby the title compound (716 mg, 58%) wasobtained.

[3083]¹H-NMR (CDCl₃) δ: 6.62 (1H, dd, J=3.4, 2.0 Hz), 7.23 (1H, d, J=3.4Hz), 7.65 (1H, d, J=2.0 Hz), 7.94 (2H, d, J=6.4 Hz), 8.77 (2H, d, J=6.4Hz), 9.03 (1H, d, J=1.5 Hz), 9.07 (1H, d, J=1.5 Hz).

[3084] MS (FAB) m/z: 224 (M+H)⁺.

Referential Example 166 5-(Pyridin-4-yl)pyrazine-2carboxylic Acid

[3085] At room temperature, potassium permanganate (700 mg) andtrioctylmethylammonium chloride (one drop) were dissolved in a mixedsolvent of water (20 ml) and benzene (20 ml). To the resulting solution,2-(furan-2-yl)-5-(pyridin-4-yl)pyrazine (700 mg) was added in portions,followed by stirring at room temperature for 17 hours. After ethanol wasadded to the reaction mixture to decompose excess potassiumpermanganate, the solvent was distilled off. To the residue, water (100ml) was added and the mixture was filtered through Celite. To thefiltrate, 1N hydrochloric acid was added to adjust its pH to 6. Thesolvent was distilled off until the precipitation of colorless crystals.The colorless crystals were collected by filtration, whereby the titlecompound (491 mg, 79%) was obtained.

[3086]¹H-NMR (DMSO-d₆ with one drop of TEA) δ: 8.61 (2H, d, J=5.9 Hz),9.04 (2H, d, J=5.9 Hz), 9.37 (1H, s), 9.66 (1H, s).

[3087] MS (FAB) m/z: 202 (M+H)⁺.

[3088] Elementary analysis for C₁₀H₇N₃O₂.0.4H₂O

[3089] Calculated: C, 57.64; H, 3.77; N, 20.16.

[3090] Found: C, 57.77; H, 3.79; N, 20.33.

Referential Example 167 4-(3-Methylpyridin-4-yl)benzoic Acid

[3091] In the same manner as in Referential Example 2, the titlecompound was obtained.

[3092]¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 7.68 (2H, d, J=8.3 Hz), 7.93(1H, d, J=5.9 Hz), 8.12 (2H, d, J=8.3 Hz), 8.85 (1H, d, J=5.9 Hz), 8.95(1H, s).

Referential Example 168 4-Amidinobenzoic Acid

[3093] In ethanol (250 ml), 4-cyanobenzoic acid (10 g) was suspended.Under ice cooling, a hydrochloric acid gas was introduced into theresulting suspension for 4 hours. After heating to room temperature, thereaction mixture was hermetically sealed and then allowed to stand for18 hours. The reaction mixture was concentrated to dryness under reducedpressure. The residue was suspended-in ethanol (250 ml) again, followedby the introduction of an ammonia gas for 4 hours under ice cooling forsaturation. After heating to room temperature, the reaction mixture washermetically sealed and allowed to stand for 3 days. To the residueobtained by distilling off the solvent under reduced pressure, dilutehydrochloric acid was added to make the residue acidic, followed byconcentration. The residue was purified by chromatography through asynthetic adsorbent (“Diaion HP-20” (trade name); water˜20%acetonitrile—water). The crude purified product so obtained wasdissolved in 20% methanol—dichloromethane and the resulting solution waspurified by chromatography on a silica gel column (20%methanol—dichloromethane). To the resulting fraction, solution ofhydrochloride in ethanol was added and the mixture was concentrated.From the concentrate, colorless crystal powder was collected byfiltration and dried, whereby ethyl 4-amidinobenzoate hydrochloride(5.25 g) was obtained as a crude purified product.

[3094] In 1N hydrochloric acid (100 ml), the resultingethyl-4-amidinobenzoate hydrochloride (3.00 g) was dissolved at roomtemperature, followed by heating under reflux for 2 hours. The solventwas then distilled off under reduced pressure. Colorless crystallinepowder so precipitated was collected by filtration and washed with asmall amount of tetrahydrofuran, whereby the title compound (2.69 g,94%) was obtained.

[3095]¹H-NMR (DMSO-d₆) δ: 7.91 (2H, d, J=8.3 Hz), 8.12 (2H, d, J=8.3Hz), 9.21 (2H, br s), 9.49 (2H, br s), 13.50 (1H, br s).

[3096] MS (FAB) m/z: 165 (M+H)⁺.

[3097] Elementary analysis for C₈H₈N₂O₂—HCl-H₂O

[3098] Calculated: C, 43.95; H, 5.07; Cl, 16.22; N, 12.81.

[3099] Found: C, 44.08; H, 5.02; Cl, 16.00; N, 12.71.

Referential Example 169 Ethyl 4-(4,5-dihydroimidazol-2-yl)benzoate

[3100] In ethanol (250 ml), 4-cyanobenzoic acid (5.00 g) was suspended.A hydrochloric acid gas was blown into the resulting suspension for 4hours under ice cooling, followed by heating to room temperature. Thereaction mixture was hermetically sealed and allowed to stand for 18hours, followed by concentration to dryness under reduced pressure. Tothe residue, diethyl ether was added. Coloress crystals thusprecipitated were collected by filtration and dried, whereby ethyl4-[1-(ethoxy)iminomethyl]benzoate hydrochloride (5.80 g, 66%) wasobtained.

[3101] The resulting ethyl 4-[1-(ethoxy)iminomethyl]benzoatehydrochloride (2.00 g) was dissolved in ethanol (30 ml). Under icecooling, ethylenediamine (0.52 ml) was added to the resulting solution,followed by heating to room temperature. The reaction mixture wasstirred overnight. To the residue obtained by distilling off the solventunder reduced pressure, dilute hydrochloric acid was added to make itacidic, followed by concentration again. The residue was purified bychromatography through a synthetic adsorbent (“Diaion HP-20”, tradename; water˜50% acetonitrile—water). Solution of hydochloride in ethanolwas added to the resulting fraction and the mixture was concentrated.Colorless crystalline powder precipitated by the addition oftetrahydrofuran was collected by filtration and dried, whereby the titlecompound (1.63 g, 19%) was obtained.

[3102]¹H-NMR (DMSO-d₆) δ: 1.35 (3H, t, J=7.3 Hz), 4.02 (4H, s), 4.37(2H, q, J=7.3 Hz), 8.17 (2H, d, J=8.8 Hz), 8.21 (2H, d, J=8.8 Hz), 11.08(2H, br s).

[3103] MS (FAB) miz: 219 (M+H)⁺.

[3104] Elementary analysis for C₁₂H₁₄N₂O₂.HCl.0.2H₂O

[3105] Calculated: C, 55.80; H, 6.01; Cl, 13.72; N, 10.84.

[3106] Found: C, 55.81; H, 5.99; Cl, 13.93; N, 11.00.

Referential Example 170 5-(4,5-Dihydroimidazol-2-yl)benzoic AcidHydrochloride

[3107] In the same manner as in Referential Example 8, a reaction waseffected using the ethyl 4-(4,5-dihydroimidazol-2-yl)benzoate as astarting material, whereby the title compound was obtained.

[3108]¹H-NMR (DMSO-d₆) δ: 4.03 (4H, s), 8.15 (4H, s), 10.99 (2H, br s).

[3109] MS (FAB) m/z: 191 (M+H)⁺.

[3110] Elementary analysis for C₁₀H₁₀N₂O₂.HCl.1.2H₂O

[3111] Calculated: C, 48.38; H, 5.44; Cl, 14.28; N, 11.28.

[3112] Found: C, 48.37; H, 5.29; Cl, 14.64; N, 11.12.

Referential Example 171 4-(4-Metylphenyl)pyridine

[3113] In the same manner as in Referential Example 2, a reaction waseffected, whereby the title compound was obtained.

[3114]¹H-NMR (CDCl₃) δ: 2.42 (3H, s), 7.30 (2H, d, J=8.3 Hz), 7.51 (2H,d, J=5.9 Hz), 7.55 (2H, d, J=8.3 Hz), 8.64 (2H, d, J=5.9 Hz).

Referential Example 172 2-Amino-4-(4-methylphenyl)pyridine

[3115] Under an argon gas, 4-(4-methylphenyl)pyridine (2.74 g) wasdissolved in N,N-dimethylaniline (10 ml), followed by the addition ofsodium amide (1.40 g) at room temperature. After the resulting mixturewas stirred at 110° C. for 2 days, the reaction mixture was cooled toroom temperature. Brown powder precipitated by the addition of water wascollected by filtration. The powder was further purified bychromatography on a silica gel column (ethyl acetate:toluene=1:1). Afterconcentration of the resulting fraction, hexane was added and powderthus precipitated was collected by filtration and dried, whereby thetitle compound (1.40 g, 47%) was obtained.

[3116]¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 4.45 (2H, br s), 6.69 (1H, d,J=1.5 Hz), 6.88 (1H, dd, J=5.4, 1.5 Hz), 7.26 (2H, d, J=8.3 Hz), 7.49(2H, d, J=8.3 Hz), 8.11 (1H, d, J=5.4 Hz)

[3117] MS (FAB) m/z: 185 (M+H)⁺.

Referential Example 173 2-Diacetylamino-4-(4-methylphenyl)pyridine

[3118] 2-Amino-4-(4-methylphenyl)pyridine (1.27 g) was dissolved indichloromethane (50 ml). Under ice cooling, N,N-diisopropylethylamine(1.80 ml) and acetyl chloride (735 μl) were successively added dropwiseto the resulting solution. After heating to room temperature, thereaction mixture was added again with N,N-diisopropylethylamine (0.90ml) and acetyl chloride (800 μl). The mixture was stirred for 18 hours.Methanol was added to the reaction mixture. Dilute hydrochloric acid andethyl acetate were then added to the residue obtained by distilling offthe solvent in order to separate the organic layer. The organic layerwas dried over anhydrous magnesium sulfate, followed by concentration.The residue was dissolved in methanol. Crystals precipitated by theaddition of water were collected by filtration and dried, whereby thetitle compound (1.39 g, 75%) was obtained.

[3119]¹H-NMR (CDCl₃) δ: 2.33 (6H, s), 2.42 (3H, s), 7.31 (2H, d, J=8.3Hz), 7.43 (1H, d, J=1.5 Hz), 7.53-7.59 (3H, m), 8.61 (1H, d, J=4.9 Hz).

[3120] MS (FAB) m/z: 269 (M+H)⁺.

[3121] Elementary analysis for C₁₆H₁₆N₂O₂

[3122] Calculated: C, 71.62; H, 6.01; N, 10.44.

[3123] Found: C, 71.28; H, 5.98; N, 10.19.

Referential Example 174 4-(2-Acetylaminopyridin-4-yl)benzoic Acid

[3124] In water (4 ml), anhydrous magnesium sulfate (161 mg) wasdissolved. To the resulting solution, the2diacetylamino-4-(4-methylphenyl)pyridine (108 mg) was suspended.Potassium permanganate (223 mg) was added to the resulting suspension,followed by heating under reflux for 2 hours. After removal of manganesedioxide, dilute hydrochloric acid and dichloromethane were added to thefiltrate to separate the water layer. The water layer was concentratedto about 20 ml and the crystals thus precipitated were collected byfiltration and dried, whereby the title compound (64 mg, 62%) wasobtained. ¹H-NMR (DMSO-d₆) δ: 2.19 (3H, s), 7.58 (1H, d, J=5.9 Hz), 7.87(2H, d, J=8.3 Hz), 8.04 (1H, s), 8.11 (2H, d, J=8.3 Hz), 8.33 (1H, s),8.43 (1H, d, J=5.9 Hz), 11.23 (1H, br s).

[3125] MS (FAB) m/z: 257 (M+H)⁺.

Referential Example 175 Methyl 4-(2-aminopyridin-4-yl)benzoate

[3126] In the same manner as in Referential Example 9, a reaction waseffected using the 4-(2-acetylaminopyridin-4-yl)benzoic acid as astarting material, whereby the title compound was obtained.

[3127]¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 4.53 (2H, br s), 6.72 (1H, d,J=1.5 Hz), 6.90 (1H, dd, J=5.4, 1.5 Hz), 7.65 (2H, d, J=8.3 Hz), 8.12(2H, d, J=8.3 Hz), 8.16 (1H, d, J=5.4 Hz).

[3128] MS (FAB) m/z: 229 (M+H)⁺.

[3129] Elementary analysis for C₁₃H₁₂N₂O₂

[3130] Calculated: C, 68.41; H, 5.30; N, 12.27.

[3131] Found: C, 68.30; H, 5.27; N, 12.36.

Referential Example 176 Methyl4-[2-(N-tert-butoxycarbonylamino)pyridin-4-yl)benzoate

[3132] In the same manner as in Referential Example 10, the titlecompound was obtained.

[3133]¹H-NMR (DMSO-d₆) δ: 1.50 (9H, s), 3.89 (3H, s), 7.38 (1H, dd,J=5.4, 1.5 Hz), 7.86 (2H, d, J=8.3 Hz), 8.10 (2H, d, J=8.3 Hz), 8.14(1H, d, J=1.5 Hz), 8.35 (1H, d, J=5.4 Hz), 9.89 (1H, br s).

Referential Example 1774-[2-(N-tert-butoxycarbonylamino)pyridin-4-yl)benzoic Acid

[3134] In the same manner as in Referential Example 11, the titlecompound was obtained.

[3135]¹H-NMR (DMSO-d₆) δ: 1.49 (9H, s), 7.38 (1H, dd, J=5.4, 1.0 Hz),7.83 (2H, d, J=8.3 Hz), 8.07 (2H, d, J=8.3 Hz), 8.12 (1H, d, J=1.0 Hz),8.33 (1H, d, J=5.4 Hz), 9.93 (1H, br s), 13.07 (1H, br s).

Referential Example 1781-[4-(2-Azidomethylpyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3136] In dichloromethane (10 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine(300 mg) was dissolved. To the resulting solution, triphenylphosphine(301 mg) and carbon tetrabromide (572 mg) were added, followed bystirring at room temperature for 5 minutes. An aqueous solution ofsodium bicarbonate and dichloromethane were added to separate theorganic layer. After the organic layer was dried over anhydrous sodiumsulfate, N,N-dimethylformamide (10 ml) was added and onlydichloromethane was distilled off. To the N,N-dimethylformamide solutioncontaining the bromo-compound, sodium azide (215 mg) was added, followedby stirring at an external temperature of about 100° C. for 90 minutes.The reaction mixture was distilled under reduced pressure to remove thesolvent. Dichloromethane and water were added to the residue to separatethe organic layer. The organic layer was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column(dichloromethane˜2% methanol—dichloromethane), whereby the titlecompound (159 mg, 51%) was obtained.

[3137]¹H-NMR (CDCl₃) δ: 3.16 (4H, br), 3.30-4.10 (4H, br), 4.57 (2H, s),7.40-7.45 (3H, m), 7.52 (1H, s), 7.60 (1H, dd, J=8.8 and 2.0 Hz), 7.64(2H, d, J=8.3 Hz), 7.76 (1H, dd, J=8.3 and 1.5 Hz), 7.90-7.96 (3H, m),8.31 (1H, d, J=1.5 Hz), 8.65 (1H, d, J=5.4 Hz)

[3138] MS (FAB) m/z: 547 [(M+H)⁺, Cl³⁵], 549 [(M+H)⁺, Cl³⁷].

Referential Example 179 Methyl 4-(2-methylpyridin-4-yl)benzoateHydrochloride

[3139] In methanol (100 ml), 4-(2-methylpyridin-4-yl)benzoic acidhydrochloride (5.00 g) was dissolved. To the resulting solution, thionylchloride (1.73 ml) was added dropwise, followed by heating under refluxfor 3.5 hours. The reaction mixture was distilled to remove the solventand pale brown crystals thus precipitated were washed with ethylacetate, whereby the title compound (4.70 g, 89%) was obtained.

Referential Example 180 Methyl 4-(2-bromomethylpyridin-4-yl)benzoate

[3140] In a mixed solution of carbon tetrachloride and an aqueoussolution of sodium bicarbonate, the methyl4-(2-methylpyridin-4-yl)benzoate hydrochloride (100 mg) was dissolved.The organic layer separated was dried over anhydrous sodium sulfate.After the insoluble matter was filtered off, N-bromosuccinic imide (68mg) and 2,2′-azoisobutylonitrile (6 mg) were added to the filtrate,followed by heating under reflux for 1 hour. The reaction mixture wasdiluted with dichloromethane, washed with water and then dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by chromatography on a silica gel column(hexane:ethyl acetate=4:1), whereby the title compound (41 mg, 35%) wasobtained.

[3141]¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 4.63 (2H, s), 7.46 (1H, dd, J=4.9,1.5 Hz), 7.68 (1H, d, J=1.5 Hz), 7.71 (2H, d, J=8.3 Hz), 8.16 (2H, d,J=8.3 Hz), 8.69 (1H, d, J=4.9 Hz).

[3142] Elementary analysis for C₁₄H₁₂BrNO₂

[3143] Calculated: C, 54.92; H, 3.95; Br, 26.10; N, 4.58.

[3144] Found: C, 54.95; H, 3.96; Br, 25.85; N, 4.33.

Referential Example 181 Methyl 4-(2-cyanomethylpyridin-4-yl)benzoate

[3145] In the same manner as in Referential Example 56, the titlecompound was obtained.

[3146]¹H-NMR (CDCl₃) δ: 3.97 (3H, s), 4.03 (2H, s), 7.51 (1H, d, J=5.4Hz), 7.67 (1H, s), 7.71 (2H, d, J=8.3 Hz), 8.17 (2H, d, J=8.3 Hz), 8.67(1H, d, J=5.4 Hz). Elementary analysys for C₁₅H₁₂N₂O₂

[3147] Calculated: C, 71.42; H, 4.79; N, 11.10.

[3148] Found: C, 71.13; H, 4.82; N, 11.05.

Referential Example 182 Methyl 4-[2-(2aminoethyl)pyridin-4-yl]benzoatedihydrochloride

[3149] In methanol (5 ml), the methyl4-(2cyanomethylpyridin-4-yl)benzoate (190 mg) was dissolved.

[3150] The resulting solution was subjected to catalytic reduction bythe addition of 10% palladium-carbon (190 mg) and concentratedhydrochloric acid (5 drops) at room temperature under normal pressurefor 24 hours. After the removal of the catalyst by filtration, thefiltrate was concentrated under reduced pressure. Ethyl acetate wasadded to the concentrate. Pale yellow crystals thus precipitate werecollected by filtration and then dried, whereby the title compound (141mg, 57%) was obtained.

[3151]¹H-NMR (DMSO-d₆) δ: 3.21-3.39 (4H, m), 3.90 (3H, s), 7.90-8.18(8H, m), 8.76 (1H, d, J=5.4 Hz).

[3152] MS (FAB) m/z: 257 (M+H)⁺.

Referential Example 183 Methyl4-[2-[2-(tert-butoxycarbonylamino)ethyl]pyridin-4-yl]benzoate

[3153] In the same manner as in Referential Example 10, the titlecompound was obtained.

[3154]¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 3.07 (2H, t, J=6.4 Hz), 3.60 (2H,q, J=6.4 Hz), 3.96 (3H, s), 5.14 (1H, br s), 7.39 (1H, dd, J=5.4 and 1.5Hz), 7.41 (1H, br s), 7.70 (2H, d, J=8.3 Hz), 8.15 (2H, d, J=8.3 Hz),8.62 (1H d, J=5.4 Hz).

[3155] MS (FAB) m/z: 357 (M+H)⁺.

Referential Example 1841-[(6-Chloronaphthalen-2-yl)sulfonyl]-6-methoxycarbonyl1,2,3,4-tetrahydropyrazine

[3156] At room temperature, 2-methoxycarbonylpyrazine (1.00 g) wasdissolved in methanol. The resulting solution was subjected to catalyticreduction by the addition of 10% palladium-carbon (100 mg) for 2 hoursunder normal pressure. After the removal of the catalyst by filtration,the solvent was distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column (5%methanol-dichloromethane), whereby6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine (880 mg, 86%) was obtainedas a yellow oil.

[3157] The resulting 6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine (440mg) was dissolved in dichloromethane (5 ml), followed by the addition ofN,N-diisopropylethylamine (594 μl) and 6-(chloronaphthalen-2-yl)sulfonylchloride (810 mg). The resulting mixture was stirred at room temperaturefor 1 hour. The reaction mixture was washed with an aqueous solution ofsodium bicarbonate, dried over anhydrous sodium sulfate and thenconcentrated. The residue thus obtained was purified by chromatographyon a silica gel column (2% methanol—dichloromethane), whereby the titlecompound (279 mg, 25%) was obtained as a pale yellow oil.

[3158]¹H-NMR (CDCl₃) δ: 3.32 (4H, s), 3.71 (3H, s), 4.68 (1H, br s),7.43 (1H, d, J=6.8 Hz), 7.55 (1H, dd, J=8.8, 2.0 Hz), 7.86-7.94 (3H, m),8.19 (1H, dd, J=8.8, 2.0 Hz), 8.54 (1H, br s).

[3159] MS (FAB) m/z: 367 [(M+H)⁺, Cl³⁵], 369 [(M+H)⁺, Cl³⁷].

[3160] Elementary analysis for C₁₆H₁₅ClN₂O₄S

[3161] Calculated: C, 52.39; H, 4.12; N, 7.64.

[3162] Found: C, 52.31; H, 4.21; N, 7.55.

Referential Example 1851-(4-Bromobenzoyl)-6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine

[3163] In the same manner as in Referential Example 184,6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine was obtained, followed byreaction with 4-bromobenzoyl chloride, whereby the title compound wasobtained.

[3164]¹H-NMR (CDCl₃) δ: 3.20-3.70 (7H, m), 4.71 (1H, br s), 7.16 (1H, d,J=6.4 Hz), 7.48 (4H, s).

[3165] MS (FAB) m/z: 325 [(M+H)⁺, Br⁷⁹], 327 [(M+H)⁺, Br⁸¹].

Referential Example 1864-(4-Bromobenzoyl)-1-[(6-chloronaphthalen-2-yl)sulfonyl-5-methoxycarbonyl-1,2,3,4-tetrahydropyrazine

[3166] In the same manner as in Example A-165, the title compound wasobtained.

[3167]¹H-NMR (CDCl₃) δ: 3.40-3.90 (7H, m), 7.33 (2H, d, J=8.3 Hz), 7.48(2H, d, J=8.3 Hz), 7.60-7.66 (2H, m), 7.79 (1H, dd, J=8.8, 2.0 Hz),7.92-7.99 (3H, m), 8.43 (1H, br s).

[3168] MS (FAB) m/z: 549 [(M+H)⁺, Br⁷⁹], 551 [(M+H)⁺, Br⁸¹].

[3169] Elementary analysis for C₂₃H₁₈BrClN₂O₅S

[3170] Calculated: C, 50.24; H, 3.30; N, 5.10; S, 5.83.

[3171] Found: C, 50.34; H, 3.37; N, 5.05; S, 5.81.

Referential Example 187 4-[3-(Aminomethyl)phenyl]benzoic AcidHydrochloride

[3172] In the same manner as in Referential Example 2, the titlecompound was obtained.

[3173]¹H-NMR (DMSO-d₆) δ: 4.11 (2H, s), 7.49-7.58 (2H, m), 7.76 (1H, d,J=6.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.92 (1H, br s), 8.05 (2H, d, J=8.3Hz).

Referential Example 1884-[3-[(tert-Butoxycarbonylamino)methyl]phenyl]benzoic Acid

[3174] In the same manner as in Referential Example 10, the titlecompound was obtained.

[3175]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 4.41 (2H, d, J=5.4 Hz), 4.94 (1H,br s), 7.28-7.37 (1H, m), 7.44 (1H, t, J=7.3 Hz), 7.50-7.60 (2H, m),7.68 (2H, d, J=8.3 Hz), 8.10-8.23 (2H, m).

Referential Example 189 Ethyl2,5-dihydro-5-oxo-3(pyridin-4-yl)-1,2,4-triazine-6-carboxylate

[3176] In ethanol (20 ml), 4-pyridinecarboxyamidrazone (1.48 g) wasdissolved. To the resulting solution, diethyl ketomalonate (1.65 ml) wasadded dropwise at room temperature, followed by stirring for 13 hours.After heating under reflux for 4 hours, the reaction mixture was cooled.Yellow crystals thus precipitated were collected by filtration anddried, whereby the title compound (1.50 g, 56%) was obtained.

[3177]¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.3 Hz), 4.36 (2H, q, J=7.3Hz), 7.98 (2H, d, J=6.3 Hz), 8.86 (2H, d, J=6.3 Hz).

[3178] MS (FAB) m/z: 247 (M+H)⁺.

[3179] Elementary analysis for C₁₁HLON₄O₃.0.2H₂O

[3180] Calculated: C, 52.88; H, 4.20; N, 22.43.

[3181] Found: C, 52.78; H, 4.36; N, 22.66.

Referential Example 1902,5-Dihydro-5-oxo-3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic Acid

[3182] In the same manner as in Referential Example 11, the titlecompound was obtained.

[3183]¹H-NMR (DMSO-d₆ (containing a small amount of trifluoroaceticacid)) δ: 8.31 (2H, d, J=6.4 Hz), 8.86 (2H, d, J=6.4 Hz).

[3184] MS (FAB) m/z: 218 (M+H)⁺.

[3185] Elementary analysis for C₉H₆N₄O₃.0.2H₂O

[3186] Calculated: C, 48.74; H, 2.91; N, 25.26.

[3187] Found: C, 48.58; H, 2.87; N, 25.21.

Referential Example 1912,6-Bis(methoxycarbonylmethyl)-1,4-dibenzylpiperazine

[3188] In a shield tube, bis(3-methoxycarbonyl-2-propylenyl)benzylamine(104 mg) and benzylamine (60.0 μl) were dissolved in methanol (5 ml).After the tube was hermetically sealed, the resultinig solution wasstirred under heat at an external temperature of about 100 to 110° C.for 63 hours. The solvent was then distilled off under reduced pressure.The residue was purified by chromatography on a silica gel column(n-hexane:ethyl acetate=3:1), whereby the title compound (123 mg, 88%)was obtained as a yellow oil.

[3189]¹H-NMR (CDCl₃) δ: 2.25-2.60 (8H, each m), 3.15-3.85 (12H, m),7.15-7.30 (10H, m).

[3190] MS (FAB) m/z: 411 (M+H)⁺.

Referential Example 192cis-2,6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3191]trans-2,6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3192] In methanol (70 ml) and hydrochloric acid (570 μl),2,6-bis(methoxycarbonylmethyl)-1,4-dibenzylpiperazine (1.33 g) wasdissolved. To the resulting solution, palladium hydroxide (149 mg) wasadded, followed by catalytic hydrogenation at room temperature for 4hours. After the removal of the catalyst by filtration, the residue wasdistilled under reduced pressure to remove the solvent. Dichloromethane(70 ml) and N,N-diisopropylethylamine (2.70 ml) were added to theresulting residue to dissolve the latter in the former, followed by theaddition of (6-chloronaphthalen-2-yl)sulfonyl chloride (495 mg). Themixture was stirred for 3 hours under stirring. To the reaction mixture,(6-chloronaphthalen-2-yl)sulfonyl chloride (200 mg) andN,N-diisopropylethylamine (180 μl) were added. The resulting mixture wasstirred for 12.5 hours, while gradually heated to room temperature froman external temperature of about 0° C. Since the reaction was notcompleted, (6-chloronaphthalen-2-yl)sulfonyl chloride (101 mg) andN,N-diisopropylethylamine (90 μl) were added further and the mixture wasstirred for 4.5 hours while heated gradually to room temperature from anexternal temperature of about 0° C. The residue obtained by distillingoff the solvent under reduced pressure was purified by chromatography ona silica gel column (5% methanol—dichloromethane, n-hexane:ethylacetate=1:2), whereby the title compounds, cis-form (226 mg, 15%) andtrans-form (1.07 g, 73%), were obtained, respectively, as pale yellowamorphous powder.

[3193]cis-2,6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3194]¹H-NMR (CDCl₃) δ: 2.00-2.10 (2H, m), 2.20-2.30 (2H, m), 2.35-2.45(2H, m), 2.85 (1H, br), 3.20-3.30 (2H, m), 3.69 (6H, s), 3.70-3.80 (2H,m), 7.50-7.60 (1H, m), 7.70-7.80 (1H, m), 7.85-7.95 (3H, m), 8.30 (1H,s).

[3195]trans-2,6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3196]¹H-NMR (CDCl₃) δ: 2.40-2.60 (5H, m), 2.80-2.90 (2H, m), 3.10-3.20(2H, m), 3.45-3.55 (2H, m), 3.69 (6H, s), 7.50-7.60 (1H, m), 7.70-7.80(1H, m), 7.85-7.95 (3H, m), 8.29 (1H, s).

[3197] MS (FAB) m/z: 455 [(M+H)⁺, Cl³⁵], 457 [(M+H)⁺, Cl³⁷].

Referential Example 193trans-2,6-Bis(methoxycarbonylmethyl)-1-(4-bromobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3198] In dichloromethane (8 ml), thetrans-2,6-bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(79.7 mg) was dissolved. Under ice cooling, N,N-diisopropylethylamine(68.0 μl) and a solution of 4-bromobenzoyl chloride (51.0 mg) indichloromethane (2 ml) were added to the resulting solution, followed bystirring at room temperature for 5.5 hours. Water was added to thereaction mixture to separate the organic layer. The organic layer waswashed with saturate aqueous NaCl solution, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column(n-hexane:ethyl acetate=1:1), whereby the title compound (113 mg, 98%)was obtained as pale yellow amorphous powder.

[3199]¹H-NMR (CDCl₃) δ: 2.80-2.90 (4H, m), 3.20-3.40 (4H, m), 3.63 (6H,s), 4.20-4.30 (2H, m), 7.23 (2H, d, J=8.3 Hz), 7.50 (2H, d, J=8.3 Hz),7.55-7.65 (1H, m), 7.70-7.80 (1H, m), 7.90-7.95 (3H, m), 8.30 (1H, s).

[3200] MS (FAB) m/z: 637 [(M+H)⁺, Br⁷⁹, Cl³⁵], 639 [(M+H)⁺, Br⁷⁹, Cl³⁷and Br⁸¹, Cl³⁵], 641 [(M+H)⁺, Br⁸¹, Cl³⁷].

Referential Example 194cis-2,6-Bis(methoxycarbonylmethyl)-1-(4-bromobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3201] In the same manner as in Referential Example 193, the titlecompound was obtained.

[3202]¹H-NMR (CDCl₃) δ: 2.40-2.75 (4H, m), 2.80-3.20 (2H, m), 3.55-4.00(2H, m), 3.68 (6H, s), 4.20-4.40 (1H, m), 5.00-5.20 (1H, m), 7.10-7.15(2H, m), 7.45-7.55 (2H, m), 7.55-7.65 (1H, m), 7.70-7.80 (1H, m),7.90-7.95 (3H, m), 8.30 (1H, s).

[3203] MS (FAB) m/z: 637 [(M+H)⁺, Br⁷⁹, Cl³⁵], 639 [(M+H)⁺, Br⁷⁹, Cl³⁷and Br⁸¹, Cl³⁵], 641 [(M+H)⁺, Br⁸¹, Cl³⁷].

Referential Example 195trans-2,6-Bis(carbamoylmethyl)-1-(4-bromobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3204] In the same manner as in Example A-35, the title compound wasobtained usingtrans-2,6-bis(methoxycarbonylmethyl)-1-(4-bromobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[3205]¹H-NMR (CDCl₃) δ: 2.5-2.65 (2H, m), 3.10-3.30 (4H, m), 3.40-3.50(2H, m), 4.20-4.30 (2H, m), 6.34 (2H, broad s), 6.59 (2H, br s), 7.14(2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.50-7.60 (1H, m), 7.65-7.75(1H, m), 7.85-7.95 (3H, m), 8.26 (1H, s).

Referential Example 196 (2-Methylpyridin-4-yl)tributyltin

[3206] Under an argon stream, diethyl ether (100 ml) was cooled to −70°C., followed by the dropwise addition of an nbutyl lithium-hexanesolution (1.52M, 14.5 ml). To the reaction mixture, a diethyl ethersolution (100 ml) containing the free form of 4-bromo-2-methylpyridinewas added dropwise over 15 minutes, followed by the dropwise addition ofa tetrahydrofuran solution (10 ml) containing tributyltin chloride (5.40ml) slowly. After stirring at −70° C. for 30 minutes, the reactionmixture was heated to room temperature and stirring was conducted for1.5 hours. Water and aqueous ammonia were added to the reaction mixtureand the reaction mixture was separated using diethyl ether. The organiclayer was dried over anhydrous magnesium sulfate, the filtrate wasconcentrated and the residue was purified by chromatography on a silicagel column (hexane:ethyl acetate=29:1→19:1), whereby the title compound(3.63 g, colorless oil substance) was obtained.

[3207]¹H-NMR (CDCl₃) δ: 0.89 (9H, t, J=7.3 Hz), 0.99-1.17 (6H, m),1.22-1.41 (6H, m), 1.50-1.65 (6H, m), 2.52 (3H, s), 7.05-7.21 (1H, m),7.22 (1H, s), 7.34-8.40 (1H, m).

[3208] MS (FAB) m/z: 382[(M+H)⁺, Sn¹¹⁸], 384[(M+H)⁺, Sn¹²⁰].

[3209] Preparation of the Free Form of 4-bromo-2-methylpyridine

[3210] By using an aqueous solution of sodium bicarbonate and diethylether, 4-bromo-2-methylpyridine hydrochlorUide (4.17 g) was separated.The organic layer was dried over anhydrous magnesium sulfate andconcentrated. Benzene was added to the concentrate, followed byconcentration again. The residue was dissolved in diethyl ether (100 ml)and the resulting solution was stored a diethyl ether solution.

Referential Example 197 (3-Fluoropyridin-4-yl)tributyltin

[3211] Under an argon stream, a solution of diisopropylamine (7.03 ml)in tetrahydrofuran (100 ml) was cooled to an internal temperature of−20° C., followed by the dropwise addition of an n-butyl lithium-hexanesolution (1.52M, 32.9 ml). After stirring at 0° C. for 1 hour, thereaction mixture was cooled to −70° C. A solution of 3-fluoropyridne(4.3 ml) in tetrahydrofuran (25 ml) was added dropwise over 30 minutes.The reaction mixture was stirred at −70° C. for 5 hours. A solution oftributyltin chloride (13.5 ml) in tetrahydrofuran (25 ml) was addeddropwise slowly and the reaction mixture was stirred for 2.5 hours. Thereaction mixture was heated to room temperature and then, separatedusing diethyl ether and water. The organic layer was dried overanhydrous magnesium sulfate, the filtrate was concentrated and purifiedby chromatography on a silica gel column (hexane:ethyl acetate=19:1),whereby the title compound (colorless oil, 18.17 g) was obtained.

[3212]¹H-NMR (CDCl₃) δ 0.89 (9H, t, J=7.3 Hz), 1.06-1.27 (6H, m),1.28-1.40 (6H, m), 1.43-1.70 (6H, m), 7.25-7.42 (1H, m), 8.30-8.40 (2H,m).

[3213] MS (FAB) m/z 386[(M+H)⁺, Sn¹¹⁸], 388[(M+H)⁺, Sn¹²⁰].

[3214] In the same manner as in Referential Example 196, compounds shownin Referential Examples 198 to 199 were synthesized.

Referential Example 198 (2,6-Dimethylpyridin-4-yl)tributyltin

[3215]¹H-NMR (CDCl₃) δ 0.89 (9H, t, J=7.3 Hz), 0.95-1.15 (6H, m),1.26-1.38 (6H, m), 1.43-1.65 (6H, m), 2.49 (6H, s), 6.97-7.07 (2H, m).

[3216] MS (FAB) m/z 396[(M+H)⁺, Sn¹¹⁸], 398[(M+H)⁺, Sn¹²⁰].

Referential Example 199 (2,5-Dimethylpyridin-4-yl)tributyltin

[3217]¹H-NMR (CDCl₃) δ 0.89 (9H, t, J=7.3 Hz), 0.95-1.20 (6H, m),1.21-1.40 (6H, m), 1.41-1.65 (6H, m), 2.30 (3H, s), 2.48 (3H, s), 7.13(1H, s), 8.24 (1H, s).

[3218] MS (FAB) m/z 396[(M+H)⁺ , Sn ¹¹⁸], 398[(M+H)⁺, Sn¹²⁰].

Referential Example 200 2,3-Dimethylpyridine N-oxide

[3219] In methylene chloride (200 ml) was dissolved 2,3-dimethylpyridine(9.50 g) and the resulting solution was cooled to 0° C.Metachloroperbenzoic acid (21.9 g) was added to the reaction mixture,followed by heating to room temperature. Stirring was conducted for 3days. An aqueous solution of sodium sulfite was added and the resultingmixture was separated using methylene chloride (200 ml). The organiclayer was dried over anhydrous magnesium sulfate, the filtrate wasconcentrated and the concentrate was purified by chromatography on asilica gel column (5% methanol—methylene chloride). Petroleum ether wasadded to the residue. Colorless powder so precipitated was collected byfiltration, followed by drying, whereby the title compound (5.47 g) wasobtained.

[3220]¹H-NMR (CDCl₃) δ 2.35 (3H, s), 2.51 (3H, s), 7.00-7.08 (2H, m),8.17 (1H, d, J=6.3 Hz)

[3221] MS (FAB) m/z 124(M+H)⁺.

Referential Example 201 2,3-Dimethyl-4-nitropyridine N-oxide

[3222] In a mixed solvent of concentrated sulfuric acid (10 ml) andfuming nitric aid (10 ml) was dissolved 2,3-dimethylpyridine N-oxide(3.73 g) at 0° C. The resulting solution was stirred at 75° C. for 1.5hours and at 100° C. for 15 minutes. The reaction mixture was charged inice water, followed by neutralization with an aqueous solution of sodiumhydroxide. The neutralized solution was separated using methylenechloride. The organic layer was dried over anhydrous magnesium sulfateand the filtrate was concentrated. Methylene chloride (1 ml) and diethylether (100 ml) were added to the residue. Pale yellow powder thusprecipitated was collected by filtration and dried, whereby the titlecompound (3.31 g) was obtained.

[3223]¹H-NMR (CDCl₃) δ 2.57 (3H, s), 2.58 (3H, s), 7.71 (1H, d, J=7.3Hz), 8.17 (1H, d, J=7.3 Hz).

[3224] MS (FAB) m/z 169(M+H)⁺.

Referential Example 202 4-Bromo-2,3-dimethylpyridine

[3225] To 2,3-Dimethyl-4-nitropyridine N-oxide (3.00 g) which had beencooled to 0° C., added was acetyl bromide (18.0 ml), followed bystirring at 50° C. for 20 minutes and then at 75° C. for 15 minutes. Thereaction mixture was charged in ice water and neutralized with anaqueous solution of ammonium carbonate. The neutralized solution wasseparated using methylene chloride. The organic layer was dried overanhydrous sodium sulfate and the filtrate was concentrated, whereby acrudely purified product of 4-bromo-2,3-dimethylpyridine N-oxide wasobtained.

[3226] The resulting product was dissolved in chloroform (50 ml),followed by cooling to 0° C. Phosphorus tribromide (5.16 ml) was addedto the reaction mixture and the resulting mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was charged in icewater and neutralized with an aqueous solution of sodium bicarbonate.Methylene chloride was added to separate the neutralized solution. Theorganic layer was dried over anhydrous sodium sulfate, the filtrate wasconcentrated and the concentrate was purified by chromatography on asilica gel column (hexane:ethyl acetate=19:1), whereby the titlecompound (1.90 g, 57%, pale yellow oil) was obtained.

[3227]¹H-NMR (CDCl₃) δ 2.40 (3H, s), 2.59 (3H, s), 7.34 (1H, d, J=5.4Hz), 8.09 (1H, d, J=5.4 Hz).

[3228] MS (EI) m/z 185 (M⁺, Br⁷⁹), 187 (M⁺, Br⁸¹).

Referential Example 203 (2,3-Dimethylpyridin-4-yl)tributyltin

[3229] In the same manner as in Referential Example 196, the titlecompound was obtained.

[3230]¹H-NMR (CDCl₃) δ 0.88 (9H, t, J=7.3 Hz), 1.01-1.18 (6H, m),1.27-1.37 (6H, m), 1.41-1.61 (6H, m), 2.31 (3H, s), 2.50 (3H, s),7.07-7.20 (1H, m), 8.19-8.24 (1H, m).

[3231] MS (FAB) m/z 396[(M+H)⁺, Sn¹¹⁸], 398[(M+H)⁺, Sn¹²⁰].

Referential Example 204 3,5-Dimethylpyridine N-oxide

[3232] In the same manner as in Referential Example 200, the titlecompound was obtained.

[3233]¹H-NMR (CDCl₃) δ: 2.28 (6H, s), 6.93 (1H, s), 7.92 (2H, s)

[3234] MS (FAB) m/z: 124 (M+H)⁺.

Referential Example 205 3,5-Dimethyl-4-nitropyridine N-oxide

[3235] In the same manner as in Referential Example 201, the titlecompound was obtained.

[3236]¹H-NMR (CDCl₃) δ: 2.32 (6H, s), 7.99 (2H, s).

[3237] MS (FAB) m/z: 169 (M+H)⁺.

Referential Example 206 4-Bromo-3,5-dimethylpyridine

[3238] In the same manner as in Referential Example 202, the titlecompound was obtained.

[3239]¹H-NMR (CDCl₃) δ: 2.38 (6H, s), 8.23 (2H, s)

[3240] MS (EI) m/z: 185 (M+, Br⁷⁹), 187 (M+, Br⁸¹)

[3241] In the same manner as in Referential Example 196, the compoundsshown in Referential Examples 207 to 211 were synthesized.

Referential Example 207 (3,5-Dimethylpyridin-4-yl)tributyltin

[3242]¹H-NMR (CDCl₃) δ: 0.88 (9H, t, J=7.3 Hz), 1.04-1.21 (6H, m),1.28-1.37 (6H, m), 1.41-1.59 (6H, m), 2.34 (6H, s), 8.13-8.18 (2H, m).

[3243] MS (FAB) m/z: 396 [(M+H)⁺, Sn¹¹⁸], 398[(M+H)⁺, Sn¹²⁰].

Referential Example 208 (6-Methylpyridin-2-yl)tributyltin

[3244]¹H-NMR (CDCl₃) δ: 0.88 (9H, t, J=7.3 Hz), 1.01-1.18 (6H, m),1.26-1.37 (6H, m). 1.43-1.63 (6H, m), 2.54 (3H, s), 6.95 (1H, d, J=7.3Hz), 7.18 (1H, d, J=7.3 Hz), 7.36 (1H, t, J=7.3 Hz).

[3245] MS (FAB) m/z: 382[(M+H)⁺ , Sn ¹¹⁸], 384[(M+H)⁺, Sn¹²⁰].

Referential Example 209 (3-Methylpyridin-4-yl)tributyltin

[3246]¹H-NMR (CDCl₃) δ: 0.89 (9H, t, J=7.3 Hz), 1.02-1.20 (6H, m),1.27-1.37 (6H, m), 1.42-1.62 (6H, m), 2.35 (3H, s), 7.22-7.34 (1H, m),8.28-8.38 (2H, m).

[3247] MS (FAB) m/z: 382 [(M+H)⁺ , Sn ¹¹⁸], 384 [(M+H)⁺, Sn¹²⁰].

Referential Example 210 (5-Methylpyridin-2-yl)tributyltin

[3248]¹H-NMR (CDCl₃) δ: 0.88 (9H, t, J=7.3 Hz), 1.02-1.19 (6H, m),1.27-1.37 (6H, m), 1.43-1.61 (6H, m), 2.29 (3H, s), 7.27-7.33 (2H, m),7.59 (1H, s).

[3249] MS (FAB) m/z: 382 [(M+H)⁺, Sn¹¹⁸], 384[(M+H)⁺, Sn¹²⁰].

Referential Example 211 (3-Methylpyridin-2-yl)tributyltin

[3250]¹H-NMR (CDCl₃) δ: 0.87 (9H, t, J=7.3 Hz), 1.05-1.23 (6H, m),1.27-1.38 (6H, m), 1.46-1.60 (6H, m), 2.36 (3H, s), 7.02 (1H, dd, J=7.8and 4.9 Hz), 7.33 (1H, d, J=7.8 Hz), 8.54 (1H, d, J=4.9 Hz).

[3251] MS (FAB) m/z: 382 [(M+H)⁺, Sn¹¹⁸], 384 [(M+H)⁺, Sn¹²⁰].

Referential Example 2121-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperidin-4-one

[3252] In N,N-dimethylformamide (10 ml) was suspended piperidin-4-one(monohydrochloric acid monohydrate, 1.54 g), followed by the addition ofdiisopropylethylamine (3.48 ml) and 6-chlorobenzo[b]thiophene-2-sulfonylchloride (2.68 g). The resulting mixture was stirred at room temperaturefor 3 days. The reaction mixture was concentrated under reducedpressure. Ethyl acetate was then added to the residue, followed bywashing with 1N hydrochloric acid. After extraction, the organic layerwas dried over anhydrous sodium sulfate and the solvent was distilledoff under reduced pressure. The residue was purified by chromatographyon a silica gel column (ethyl acetate:methylene chloride=3:1), followedby washing with hexane, whereby the title compound (colorless prismcrystals, 1.92 g) was obtained.

[3253]¹H-NMR (CDCl₃) δ: 2.59 (4H, d, J=6.4 Hz), 3.55 (4H, d, J=6.4 Hz),7.45 (1H, dd, J=8.8, 2.0 Hz), 7.80-7.84 (2H, m), 7.87 (1H, d, J=2.0 Hz).

[3254] MS (FAB) m/z: 330 [(M+H)⁺, Cl³⁵], 332 [(M+H)⁺, Cl³⁷].

Referential Example 2134-(4-Bromobenzylidene)-1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperidine

[3255] In a mixed solvent of tetrahydrofuran (10 ml) and ethanol (10 ml)was dissolved 4-bromobenzyl triphenylphosphonium bromide (512 mg). Theresulting solution was cooled to 0° C., followed by the successiveaddition of sodium hydride (60% in oil, 40 mg) and1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperidin-4-one (297 mg). Theresulting mixture was stirred at room temperature for 16 hours and at50° C. for 9 hours. Saturated aqueous NaCl solution and ethyl acetatewere added to the reaction mixture to separate the same. The resultingorganic layer was dried over anhydrous magnesium sulfate, the filtratewas concentrated and the residue was purified by chromatography on asilica gel column (hexane:ethyl acetate=4:1), whereby the title compound(colorless powder, 133 mg) was obtained.

[3256]¹H-NMR (CDCl₃) δ: 2.48 (2H, d, J=5.9 Hz), 2.57 (2H, d, J=5.9 Hz),3.16 (2H, d, J=5.9 Hz), 3.28 (2H, d, J=5.9 Hz), 6.25 (1H, s), 6.97 (2H,d, J=8.3 Hz), 7.40-7.45 (3H, m), 7.73 (1H, s), 7.79 (1H, d, J=8.5 Hz),7.84 (1H, d, J=1.2 Hz).

Referential Example 214 6-Bromobenzo[b]thiophene

[3257] To quinoline (45 ml) were added 6-bromobenzothiophene2-carboxylicacid (14 g) and copper powder (874 mg), followed by stirring under heatat an oil temperature of 220° C. for 2 hours. After the reaction mixturewas allowed to cool down, ether was added and the copper powder wasfiltered off. The filtrate was washed with a 1N aqueous solution ofhydrochloric acid, then with a 1N aqueous solution of sodium hydroxideand finally with saturated aqueous NaCl solution, followed by dryingover anhydrous sodium sulfate. The solvent was then distilled off underreduced pressure. The residue was purified by chromatography on a silicagel column (hexane), whereby the title compound (5.56 g) was obtained asa pale yellow solid. In addition, the raw material (3.15 g) wasrecovered.

[3258]¹H-NMR (CDCl₃) δ: 7.29 (1H, d, J=5.4 Hz), 7.42 (1H, d, J=5.4 Hz),7.46 (1H, dd, J=8.3, 1.5 Hz), 7.67 (1H, d, J=8.3 Hz), 8.01 (1H, d, J=1.5Hz).

[3259] MS (EI) m/z: 214 (M⁺, ⁸¹Br), 212 (M⁺, ⁷⁹Br)

Referential Example 215 6-Trimethylsilylethynylbenzo[b]thiophene

[3260] In tetrahydrofuran (15 ml) was dissolved 6-bromobenzo[b]thiophene(2.13 g), followed by the addition of triphenylphosphine (787 mg),triethylamine (40 ml), N,N-dimethylformamide (15 ml),trimethylsilylacetylene (1.47 g) and palladium acetate (225 mg). Theresulting mixture was refluxed for 5 hours. After the reaction mixturewas allowed to cool down, it was diluted with methylene chloride (150ml). The diluted mixture was washed with water (twice) and saturatedaqueous NaCl solution, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (only hexane), whereby thetitle compound (1.38 g) was obtained.

[3261]¹H-NMR (CDCl₃) δ: 0.27 (9H, s), 7.30 (1H, d, J=5.7 Hz), 7.44 (1H,dd, J=8.3, 1.0 Hz), 7.49 (1H, d, J=5.7 Hz), 7.73 (1H, d, J=8.3 Hz), 8.00(1H, s).

[3262] MS (EI) m/z: 230 M⁺.

Referential Example 2166-Trimethylsilylethynylbenzo[b]thiophene-2-sulfonyl Chloride

[3263] In anhydrous diethyl ether (10 ml) was dissolved6-trimethylsilylethynylbenzo[b]thiophene (408 mg). After the resultingsolution was cooled to −78° C., tert-butyl lithium (a 1.54 mole pentanesolution, 1.15 ml) was added dropwise. The reaction mixture was heatedto 0° C. over 30 minutes, followed by stirring for 1 hour. The reactionmixture was cooled again to −79° C. and then, a sulfurdioxide gas wasintroduced thereinto. After heating to room temperature over 1 hour, themixture was stirred for 1 hour. The unreacted portion of sulfurdioxidegas which had been dissolved in the reaction mixture was volatilizedsufficiently. The solvent was then distilled off under reduced pressure.Hexane (20 ml) was added to the residue. An insoluble precipitate wascollected by filtration and washed with hexane. The precipitate was thendissolved in methylene chloride (10 ml). After cooling to 0° C.,N-chlorosuccinic imide (248 mg) was added and the resulting mixture wasstirred for 30 minutes and after heating to room temperature, stirredfor further 1 hour. Water was added to the reaction mixture to separateit into layers. The water layer was extracted with methylene chloride (5times each with a 10 ml portion). The organic layers were combined,washed with saturated aqueous NaCl solution, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent,whereby the title compound (498 mg) was obtained as a pale yellow solid.

[3264]¹H-NMR (CDCl₃) δ: 0.28 (9H, s), 7.58 (1H, dd, J=8.3, 1.5 Hz), 7.89(1H, d, J=8.3 Hz), 8.02 (1H, s), 8.10 (1H, s).

[3265] MS (EI) m/z: 328 M⁺.

Referential Example 2171-[(6-Trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl-3]-(N-methylcarbamoyl)piperazine

[3266] In methanol (15 ml) was dissolved1,4-dibenzyl-2-(N-methylcarbamoyl)piperazine (437 mg). Palladiumhydroxide (22 mg) and concentrated hydrochloric acid (0.22 ml) were thenadded to the resulting solution. A hydrogen gas was introduced (1atmospheric pressure) into the resulting mixture, followed by stirringat room temperature for 1 hour. After the addition of triethylamine (0.9ml), palladium was filtered off and the solvent was distilled off underreduced pressure. The residue was dissolved in methylene chloride.Triethylamine (0.5 ml) was added to the resulting mixture, followed bythe addition of 6-trimethylsilylethynylbenzo[b]thiophene-2-sulfonylchloride (399 mg) under ice cooling. After the temperature was allowedto rise back to room temperature, stirring was conducted for 20 hours.The reaction mixture was washed (twice) with a saturated aqueoussolution of sodium bicarbonate, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (methanol:methylenechloride=1:19), whereby the title compound (462 mg) was obtained as apale yellow solid.

[3267]¹H-NMR (CDCl₃) δ: 0.28 (9H, s), 1.52 (1H, br s), 2.57-2.66 (2H,m), 2.80, 2.79(total 3H, each s), 2.97 (1H, dt, J=3.3, 11.5 Hz), 3.09(1H, dt, J=13.2, 3.1 Hz), 3.51 (1H, dd, J9.8, 3.4 Hz), 3.59 (1H, dd,J=11.7, 0.98 Hz), 3.92 (1H, dd, J=11.7, 2.4 Hz), 6.56-6.57 (1H, m), 7.52(1H, dd, J=8.3, 0.98 Hz), 7.77 (1H, s), 7.82 (1H, d, J=8.3 Hz), 7.97(1H, s).

[3268] MS (FAB) m/z: 436 (M+H)⁺.

Referential Example 2181-(tert-Butoxycarbonyl)-4-[(5-bromopyridin-2-yl)carbonyl]piperazine

[3269] In the same manner as in Referential Example 3, the titlecompound was obtained.

[3270]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.35-3.37 (2H, m), 3.45-3.48 (2H,m), 3.54-3.57 (2H, m), 3.77-3.79 (2H, m), 8.87 (2H, s).

[3271] MS (FAB) m/z: 373 [(M+H)⁺, ⁸¹Br], 371 [(M+H)⁺, ⁷⁹Br].

Referential Example 2191-(tert-Butoxycarbonyl)-4-[[5-(4-pyridyl)pyrimidin-2-yl]carbonyl]piperazine

[3272] To a mixed solvent of dimethoxyethane (60 ml) and methanol (120ml) were added1-(tert-butoxycarbonyl)-4-[(5-bromopyrimidin-2-yl)carbonyl]piperazine(2.97 g), (pyridin-4-yl)boronic acid (1.48 g), cesium fluoride (4.25 g)and tetrakis(triphenylphosphine)palladium (924 mg). After purging withargon, the reaction mixture was refluxed for 19 hours. The solvent wasthen distilled off under reduced pressure. The residue was purified bymoderate-pressure chromatography on a silica gel column (size D,methanol methylene chloride=1:9), whereby the title compound (1.31 g)was obtained as a colorless solid.

[3273]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.40-3.44 (2H, m), 3.48-3.52 (2H,m), 3.59 (2H, t, J=5.4 Hz), 3.84 (2H, t, J=5.4 Hz), 7.54 (2H, dd, J=4.4,2.0 Hz), 8.81 (2H, dd, J=4.4, 2.0 Hz), 9.07 (2H, s).

[3274] MS (FAB) m/z: 369 M⁺.

Referential Example 2201-[(5-Chloro-lphenylsulfonylindol-2-yl)sulfonyl]-3-(methoxycarbonylmethyl)piperazine

[3275] To an ethanol solution (50 ml) of1-(tert-butoxycarbonyl)-3-(3-methoxycarbonylmethyl)piperazine (5.03 g)was added a saturated solution of hydrochloride in ethanol (20 ml),followed by stirring for 30 minutes. After the solvent was distilled offunder reduced pressure, the residue was dissolved in methylene chlorideto obtain a methylene chloride solution (200 ml). At room temperature,5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (7.64 g) andtriethylamine (9.5 ml) were added to the resulting solution, followed bystirring at room temperature for 4 hours. Distilled water and methylenechloride were added and the water layer was extracted three times. Theorganic layers were combined, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue soobtained was subjected to chromatography on a silica gel column(methanol:methylene chloride=1:50), whereby the title compound (4.97 g)was obtained as a

[3276] MS (FAB) m/z: 512 [(M+H)⁺, Cl³⁵], 514 [(M+H)⁺, Cl³⁷].

[3277]¹H-NMR (CDCl₃) δ: 2.15-2.30 (1H, br), 2.34-2.49 (2H, m), 2.72-2.76(1H, m), 2.90-3.22 (3H, m), 3.17-3.25 (1H, m), 3.67 (3H, s), 3.71-3.77(2H, m), 7.39-7.47 (4H, m), 7.52-7.58 (2H, m), 8.02 (2H, d, J=7.8 Hz),8.23 (1H, d, J=9.3 Hz).

Referential Example 2211-(tert-Butoxycarbonyl)-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)piperazine

[3278] To an ethanol solution (250 ml) of1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(methoxycarbonylmethyl)piperazine(2.00 g) was added ditert-butyl dicarbonate (3.91 g) at roomtemperature, followed by stirring for 17 hours. The reaction mixture wasconcentrated under reduced pressure and diethyl ether was added to theconcentrate. The crystals thus precipitated were collected byfiltration, washed with diethyl ether and dried under reduced pressure,whereby the title compound (2.01 g) was obtained as colorless crystals.

[3279] MS (FAB) m/z: 612 [(M+H)⁺, Cl³⁵], 614 [(M+H)⁺, Cl³⁷].

[3280]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.45-2.54 (1H, m), 2.74-2.86 (1H,m), 2.92-3.03 (1H, m), 3.07-3.27 (1H, m), 3.37 (3H, s), 3.67-3.77 (2H,m), 3.94-4.06 (2H, m), 4.52-4.67 (1H, m), 7.38-7.49 (4H, m), 7.57-7.60(2H, m), 8.03 (2H, d, J=6.8 Hz), 8.23 (1H, d, J=9.3 Hz).

Referential Example 2221-(tert-Butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)]carbonyl]methyl]piperazine

[3281] To a 1,4-dioxane solution (100 ml) of1-(tert-butoxycarbonyl)-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)piperazine(1.0 g) was added a 1N aqueous solution (4.9 ml) of sodium hydroxide atroom temperature. The resulting mixture was heated to 80° C. and stirredfor 6 hours. Under ice cooling, a saturated aqueous solution of ammoniumchloride was added to neutralize the reaction mixture, followed byaddition of distilled water. The water layer was extracted four timeswith methylene chloride. The organic layers were combined, dried overanhydrous sodium sulfate, and distilled under reduced pressure to removethe solvent. The residue was dissolved in methylene chloride to obtain amethylene chloride solution (150 ml). To the resulting solution wereadded 1-hydroxybenzotriazole (0.24 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g),morpholine (0.16 g) and N-methylmorpholine (0.41 g), followed bystirring at room temperature for 12 hours. Distilled water was added tothe reaction mixtrue. The water layer was extracted three times withmethylene chloride. The organic layers were combined, washed four timeswith distilled water, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The resulting residue wassubjected to chromatography on a silica gel column (methanol:methylenechloride 1:50), whereby the title compound (0.71 g) was obtained as acolorless solid.

[3282]¹H-NMR (MHz, CDCl₃) δ: 1.41 (9H, s), 2.23-2.30 (3H, m), 3.34-3.84(12H, m), 3.91-4.12 (1H, m), 4.49-4.64 (1H, m), 6.98 (1H, s), 7.27-7.33(1H, m), 7.37 (1H, d, J=8.8 Hz), 7.66 (1H, s).

[3283] MS (FAB) m/z: 527 [(M+H)⁺, Cl³⁵], 529 [(M+H)⁺, Cl³⁷].

Referential Example 2231-(tert-Butoxycarbonyl)-2-(carbamoylmethyl)-[(5-chloroindol-2-yl)sulfonyl]piperazine

[3284] To a 1,4-dioxane solution (100 ml) of1-(tert-butoxycarbonyl)-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)piperazine(800 mg) was added a 1N aqueous solution of sodium hydroxide (3.9 ml) atroom temperature. The resulting mixture was heated to 80° C. and stirredfor 13 hours. Under ice cooling, a saturated aqueous solution ofammonium chloride was added to neutralize the reaction mixture, followedby the addition of distilled water and methylene chloride. The waterlayer was extracted 4 times with methylene chloride. The organic layerswere combined, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was dried overnightunder reduced pressure and then, an N,N′-dimethylformamide solution (50ml) was obtained. At room temperature, ditert-butyl dicarbonate (856 mg,3.92 mmol), pyridine (259 mg) and ammonium bicarbonate (233 mg) wereadded to the resulting solution, followed by stirring at roomtemperature for 15 hours. The reaction mixture was distilled underreduced pressure to remove the solvent and the residue was dissolved inmethylene chloride. Hexane and diethyl ether were added to solidify theresulting solution. The resulting solid was collected by filtration,washed with hexane and dried under reduced pressure, whereby the titlecompound (502 mg) was obtained as a colorless solid.

[3285] MS (FAB) m/z: 457 [(M+H)⁺, Cl³⁵], 459 [(M+H)⁺, Cl³⁷]

[3286]¹H-NMR (MHz, CDCl₃) δ: 0.88 (1H, t, J=6.4 Hz), 1.24-1.33 (1H, m),1.35-1.44 (1H, m), 1.46 (9H, s), 2.32-2.59 (2H, m), 2.88-3.18 (2H, m),3.69-3.88 (1H, m), 3.91-4.16 (1H, m), 4.35-4.82 (1H, m), 5.91-6.60 (1H,m), 6.97 (1H, s), 7.26-7.29 (1H, m), 7.41 (1H, d, J=8.8 Hz), 7.66 (1H,s).

Referential Example 224 1,4-Dibenzyl-2-ethenylpiperazine

[3287] After a solution of 1,4-dibenzyl-2-(ethoxycarbonyl)piperazine(6.76 g) in methylene chloride (250 ml) was cooled to −78° C.,diisobutylaluminum hydride (a 1.0 mol/l hexane solution, 39.90 ml) wasadded dropwise and the mixture was stirred at −78° C. for 2 hours. Asaturated aqueous solution of ammonium chloride and methylene chloridewere added to the reaction mixture. The water layer was extracted threetimes. The organic layers were combined, washed with distilled water anddried over anhydurous sodium sulfate. The residue obtained by distillingoff the solvent under reduced pressure was provided for the subsequentreaction without purification. After cooling a tetrahydrofuran solution(150 ml) of methyltriphenylphosphonium iodide (8.07 g) to −78° C.,nbutyl lithium (a 1.52 mole hexane solution, 13.14 ml) was addeddropwise and the mixture was stirred at −78° C. for 2 hours. A solutionof the residue, which residue had been obtained above, intetrahydrofuran was then added. The reaction mixture was heated from−78° C. to 0° C. while stirring for 4 hours and then, a saturatedaqueous solution of ammonium chloride was added to terminate thereaction. Diethyl ether was added and the water layer was extractedthree times. The organic layers were combined, washed with saturatedaqueous NaCl solution and dried over anhydrous magnesium sulfate. Theresidue obtained by distilling off the solvent under reduced pressurewas subjected to chromatography on a silica gel column(methanol:methylene chloride=1:50), whereby the title compound (3.22 g)was obtained as a pale yellow oil.

[3288] MS (EI) m/z: 292 M⁺.

[3289]¹H-NMR (CDCl₃) δ: 2.07-2.22 (3H, m), 2.62-2.76 (3H, m), 2.89-2.97(1H, m), 3.07 (1H, d, J=13.2 Hz), 3.43-3.56 (2H, m), 4.04 (1H, d, J=13.2Hz), 5.15-5.32 (2H, m), 5.77-5.88 (1H, m), 7.20-7.33 (10H, m).

Referential Example 225 2-Ethylpiperazine Hydrochloride

[3290] At room temperature, concentrated hydrochloric acid (6 ml) andpalladium hydroxide (1.1 g) were added to solution (600 ml) of1,4-dibenzyl-2-ethenylpiperazine (10.9 g) in ethanol, followed bystirring for 12 hours under a hydrogen gas stream of 1 atmosphericpressure. The catalyst was filtered off and the solvent was distilledoff under reduced pressure. The resulting residue was solidified usingmethylene chloride—diethyl ether, followed by washing with diethylether. The resulting solid was dried under reduced pressure, whereby thetitle compound (6.516 g) was obtained as a brown solid.

[3291] MS (EI) m/z: 114 M⁺.

[3292]¹H-NMR (DMSO-d₆) δ: 0.95 (3H, t, J=7.8 Hz), 1.56-1.79 (2H, m),₂₀.95-3.07 (1H, m), 3.15-3.54 (6H, m), 9.75 (4H, br).

Referential Example 2261-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(ethyl)piperazine

[3293] To a methylene chloride solution (700 ml) of 2ethylpiperazinehydrochloride (5.00 g) were added5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (7.14 g) andtriethylamine (11.16 ml) and the resulting mixture was stirred at roomtemperature for 3 hours. Distilled water and methylene chloride wereadded and the water layer was extracted three times. The organic layerswere combined, dried over anhydrous sodium sulfate and distilled underreduceu pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (methanol:methylenechloride=1:100), whereby the title compound (5.86 g) was obtained as apale yellow oil.

[3294] MS (EI) m/z: 468 (M⁺, Cl³⁵), 470 (M⁺, Cl³⁷).

[3295]¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.8 Hz), 1.33-1.46 (2H, m),₂₀.53-2.62 (1H, m), 2.56-2.74 (1H, m), 2.87-3.07 (3H, m), 3.75-3.83 (2H,m), 7.38 (1H, s), 7.40-7.47 (3H, m), 7.53-7.57 (2H, m), ₈₀.00-8.05 (2H,m), 8.22 (1H, d, J=8.8 Hz).

Referential Example 2271-[(5-Chloroindol-2-yl)sulfonyl]-3-(ethyl)piperazine

[3296] A 1N aqueous solution (16 ml) of sodium hydroxide was added to a1,4-dioxane solution (200 ml) of1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(ethyl)piperazine(3.78 g) and the resulting mixture was stirred at 80° C. for 11.5 hours.A saturated aqueous solution of ammonium chloride was added to thereaction mixture. Distilled water and ethyl acetate were then added andthe water layer was extracted three time. The organic layers werecombined, dried over anhydrous magnesium sulfate and distilled underreduced pressure to remove the solvent. The residue was subjected tochromatography on a silica gel column (methanol:methylenechloride=1:100), followed by crystallization fromtetrahydrofuran—diethyl ether, whereby the title compound (2.54 g) wasobtained as needle crystals.

[3297]¹H-NMR (MHz, CDCl₃) δ: 0.92 (3H, t, J=7.8 Hz), 1.25-1.42 (2H, m),2.09 (1H, t, J=1.3 Hz), 2.47 (1H, dt, J=2.9, 11.2 Hz), 2.63-2.72 (1H,m), 2.92 (1H, dt, J=2.9, 17.2 Hz), 3.00-3.07 (1H, m), 3.60-3.70 (2H, m),6.95 (1H, s), 7.30 (1H, dd, J=8.8, 1.9 Hz), 7.37 (1H, d, J=8.8 Hz), 7.67(1H, d, J=1.9 Hz), 8.98 (1H, br).

Referential Example 2281-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-ethylpiperazine

[3298] To an N,N-dimethylformamide solution (200 ml) of1[(5-chloroindol-2-yl)sulfonyl]-3-(ethyl)piperazine (2.54 g) were addedbenzotriazol-1-yl-oxo-tris-pyrrolidinophosphonium hexafluorophosphite(4.84 g), 5-bromopyrimidine-2-carboxylic acid (1.83 g) and triethylamine(1.40 ml). The resulting mixture was stirred at room temperature for 12hours. Distilled water was added and the water layer was extracted threetimes with ethyl acetate. The organic layers were combined, washed threetimes with distilled water, dried over anhydrous magnesium sulfate anddistilled under reduced pressure to remove the solvent. The residue wassubjected to chromatography on a silica gel column (methanol:methylenechloride=1:100), followed by crystallization from methylene chloride andwashing with diethyl ether, whereby the title compound (3.18 g) wasobtained as a colorless solid.

[3299] MS (FAB) m/z=512 (M+), 514 [(M+2)+], 516 [(M+4)+].

[3300]¹H-NMR (MHz, CDCl₃) δ: 0.83 (1.5H, t, J=7.3 Hz), 1.03(1.5H, t,J=7.3 Hz), 1.74-2.02 (2H, m), 2.48-2.70 (2H, m), 3.16-3.25(0.5H, m),3.40-3.53 (1H, m), 3.58(0.5H, m), 3.67 (1H, t, J=11.0 Hz), 3.79-3.92(1H, m), 4.65-4.70(0.5H, m), 4.78-4.85(0.5H, m), 6.94 (1H, s), 7.33-7.39(1H, m), 7.68 (1H, s), 8.79 (1H, s), 8.83 (2H, s).

Referential Example 2291-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-3-(ethyl)piperazine

[3301] To a methylene chloride solution (30 ml) of 2ethylpiperazinehydrochloride (307 mg) was added (6-chlorobenzo[b]thien-2-yl)sulfonylchloride (438 mg) and triethylamine (498 mg). The resulting mixture wasstirred at room temperature for 26 hours. Distilled water and methylenechloride were added and the water layer was extracted three times. Theorganic layers were combined, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue wassubjected to chromatography on a silica gel column (methanol:methylenechloride=1:20), whereby the title compound (255 mg) was obtained as apale yellow oil.

[3302] MS (FAB) m/z: 345 [(M+H)⁺, Cl³⁵], 347 [(M+H)⁺, Cl³⁷].

[3303]¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.8 Hz), 1.24-1.46 (2H, m), 2.16(1H, t, J=10.7 Hz), 2.54 (1H, dt, J=2.9, 11.2 Hz), 2.65-2.75 (1H, m),2.95 (1H, dt, J=2.9, 11.2 Hz), 3.04-3.10 (1H, m), 3.65-3.72 (2H, m),7.43 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, s), 7.81 (1H, d, J=8.8 Hz), 7.86(1H, s).

Referential Example 2301-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-ethylpiperazine

[3304] Under an argon atmosphere, N,N-dimethylformamide (0.15 ml) wasadded to a methylene chloride solution (25 ml) of5-bromopyrimidine-2-carboxylic acid (455 mg) was added and the resultingmixture was ice cooled. Oxalyl chloride (564 mg) was added and theresulting mixture was stirred for 30 minutes under ice cooling. Theresulting solution, together with diisopropylethylamine (2.7 ml), wasadded to a methylene chloride solution (25 ml) of1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-3-ethylpiperazine (255 mg),followed by stirring at 0° C. for 1 hour. The reaction mixture was addedsuccessively with a saturated aqueous solution of ammonium chloride anddistilled water. The water layer was extracted three times withmethylene chloride. The organic layers were combined, washed three timeswith distilled water, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was subjectedto chromatography on a silica gel column (methanol:methylenechloride=1:100), whereby the title compound (308 mg) was obtained as apale yellow oil.

[3305] MS (FAB) m/z=529 (M⁺), 531 [(M+2)⁺], 533 [(M+4)⁺].

[3306]¹H-NMR (CDCl₃) δ: 0.84(1.5H, t, J=7.3 Hz), 1.05(1.5H, t, J=7.3Hz), 1.17-2.03(0.5H, m), 1.76-2.04 (2H, m), 2.55-2.77(2.5H, m),3.17-3.28 (1H, m), 3.40-3.62 (1.5H, m), 3.67-3.77 (1H, m), 3.82-3.94(1H, m), 4.65-4.70(0.5H, m), 4.80-4.87(0.5H, m), 7.45 (1H, dd, J=8.8,2.0 Hz), 7.75 (1H, s), 7.82 (1H, d, J=8.8 Hz), 7.87 (1H, br), 8.83 (2H,s).

Referential Example 231 1,4-Dibenzyl-2-(2-methyl-1-propenyl)piperazine

[3307] After cooling a methylene chloride solution (400 ml) of1,4-dibenzyl-2-ethoxycarbonylpiperazine (19.57 g) to 78° C.,diisobutylaluminum hydride (a 0.95 mole hexane solution, 121.7 ml) wasadded dropwise. The resulting mixture was stirred at −78° C. for 2.5hours. A saturated aqueous solution of ammonium chloride and methylenechloride were added and then, the water layer was extracted three times.The organic layers were combined, washed with distilled water and driedover anhydrous sodium sulfate. The residue obtained by distilling offthe solvent under reduced pressure was provided for the subsequentreaction without purification. After cooling a tetrahydrofuran solution(300 ml) of isopropyltriphenylphosphonium iodide (25.0 g) to −78° C.,n-butyl lithium (a 1.53 mole hexane solution, 37.8 ml) was addeddropwise, followed by stirring at −78° C. for 30 minutes. A solution ofthe residue, which had been obtained above, in tetrahydrofuran was addeddropwise to the reaction mixture. The resulting mixture was heatedgradually from −78° C. and stirred overnight. A saturated aqueoussolution of ammonium chloride was added to terminate the reaction. Ethylacetate was added and the water layer was extracted three times. Theorganic layers were combined, washed with saturated aqueous NaClsolution and dried over anhydrous magnesium sulfate. The residueobtained by distilling off the solvent under reduced pressure Theresidue was subjected to chromatography on a silica gel column (ethylacetate:hexane=1:20), whereby the title compound (6.0 g) was obtained asa pale yellow oil.

[3308] MS (EI) m/z: 320 M⁺.

[3309]¹H-NMR (CDCl₃) δ: 0.88 (3H, s), 0.91 (3H, s), 2.00 (1H, t, J=10.7Hz), 2.04-2.21 (2H, m), 2.64-2.72 (3H, m), 3.00-3.18 (2H, m), 3.40-3.55(2H, m), 4.06 (1H, d, J=13.7 Hz), 5.13 (1H, d, J=8.8 Hz), 7.16-7.45(10H, m).

Referential Example 232 2-(2-Methylpropyl)piperazine Hydrochloride

[3310] Concentrated hydrochloric acid (3 ml) and palladium hydroxide(683 mg) were added to an ethanol solution (300 ml) of1,4-dibenzyl-2-(2-methyl-1-propenyl)piperazine (5.2 g), followed bystirring for 2 hours under a hydrogen gas stream of 1 atmosphericpressure. The catalyst was removed by filtration and the solvent wasdistilled off under reduced pressure. The residue was recrystallizedfrom methylene chloride—hexane, followed by washing with diethyl etherand drying under reduced pressure, whereby the title compound (2.95 g)was obtained as a brown solid.

[3311] MS (EI) m/z: 143 M⁺.

[3312]¹H-NMR (DMSO-d₆) δ: 0.86-1.30 (1H, m), 1.73 (3H, s), 1.76 (3H, s),3.10-3.47 (7H, m), 4.36-4.45 (1H, m), 5.18 (1H, d, J=9.3 Hz)

Referential Example 2331-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine

[3313] To a methylene chloride solution (150 ml) of2-(2-methylpropyl)piperazine hydrochloride (1.50 g) were added5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (2.72 g) andtriethylamine (2.91 ml). The resulting mixture was stirred at roomtemperature for 13 hours. Distilled water and methylene chloride wereadded and the water layer was extracted three times. The organic layerswere combined, washed with saturated aqueous NaCl solution, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was subjected to chromatography on a silica gelcolumn (methanol:methylene chloride=1:20), whereby the title compound(2.69 g) was obtained as a brown oil.

[3314] MS (FAB) m/z: 496 [(M+H)⁺, Cl³⁵], 498 [(M+H)⁺, Cl³⁷).

[3315]¹H-NMR (CDCl₃) δ: 0.89 (1H, t, J=5.9 Hz), 1.50-1.52 (1H, m),2.70-2.79 (1H, m), 2.90-3.12 (3H, m), 3.55-3.83 (3H, m), 5.02 (1H, d,J=8.3 Hz), 7.35-7.48 (4H, m), 7.51-7.58 (2H, m), 8.02 (2H, d, J=8.3 Hz),8.22 (1H, d, J=8.8 Hz).

Referential Example 2341-[(5-Chloroindol-2-yl)sulfonyl-3-(2-methylpropyl)piperazine

[3316] To a solution of1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine(2.57 g) in a mixture of 1,4-dioxane and distilled water (100-10 ml) wasadded a 1N aqueous solution (10.4 ml) of sodium hydroxide. The resultingmixture was stirred at 80° C. for 3 days. After saturated ammoniumchloride was added to terminate the reaction, distilled water and ethylacetate were added. The water layer was extracted three times. Theorganic layers were combined, dried over anhydrous magnesium sulfate anddistilled under reduced pressure to remove the solvent. The residue wassubjected to chromatography on a silica gel column (methanol:methylenechloride=1:50), whereby the title compound (0.93 g) was obtained as abrown oil.

[3317] MS (FAB) m/z: 356 [(M+H)⁺, Cl³⁵], 358 [(M+H)⁺, Cl³⁷].

[3318]¹H-NMR (CDCl₃) δ: 0.78-1.30 (2H, m), 1.69 (3H, s), 1.70 (3H, s),1.63-1.80 (1H, m), 2.39-2.55 (1H, m), 2.90-3.07 (2H, m), 3.48-3.70 (3H,m), 4.90 (1H, d, J=8.3 Hz), 6.92-6.99 (1H, m), 7.31 (1H, dd, J=8.8, 2.0Hz), 7.36 (1H, d, J=8.8 Hz), 7.65-7.69 (1H, m), 8.72 (1H, br).

Referential Example 2351-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(2-methylpropyl)piperazine

[3319] To an N,N-dimethylformamide solution (60 ml) of1-[(5-chloroindol-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine (0.91 g)were added benzotriazol-1-yl-oxo-tris-pyrrolidino-phosphoniumhexafluorophosphite (1.60 g), 5-bromopyrimidine-2-carboxylic acid (0.63g) and triethylamine (0.39 g). The resulting mixture was stirred at roomtemperature for 14 hours. The solvent was then distilled off underreduced pressure. Distilled water was added to the residue and the waterlayer was extracted three times with methylene chloride. The organiclayers were combined, washed three times with distilled water, driedover anhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent. The residue was subjected to chromatography on asilica gel column (methanol:methylene chloride=1:100), followed bycrystallization from ethanol—diethyl ether, whereby the title compound(0.47 g) was obtained as brown crystals.

[3320] MS (FAB) m/z=538 (M⁺), 540 [(M+2)⁺], 542 [(M+4)⁺].

[3321]¹H-NMR (CDCl₃) δ: 0.70-1.28 (2H, m), 1.60-1.75 (1H, m), 1.79 (3H,s), 1.82 (3H, s), 2.53-2.90 (2H, m), 3.34-3.48(0.5H, m),3.53-3.62-(0.5H, m), 3.68-3.79 (1H, m), 3.83-3.97(0.5H, m),4.54-4.66(0.5H, m), 5.64 (1H, br), 6.95 (1H, br), 7.34 (1H, dd, J=8.8,2.0 Hz), 7.38 (1H, d, J=8.8 Hz), 7.69 (1H, s), 8.73 (1H, s), 8.82 (2H,br).

Referential Example 236 3-(5-Thiazolyl)pyridine

[3322] At room temperature, tetrakis(triphenylphosphine)palladium (470mg) was added to 3-bromopyridine (805 μl) and a solution of(5-thiazolyl)trimethyltin (2.07 g) in benzene (80 ml), followed byheating under reflux overnight. After the reaction mixture was allowedto cool down to room temperature, it was washed with a saturated aqueoussolution (100 ml) of sodium bicarbonate. The water layer was extractedwith ethyl acetate (3×20 ml). The organic layers were combine, driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was purified by chromatography on asilica gel column (hexane:ethyl acetate=2:1), whereby the title compound(1.68 g, purity: 85%) was obtained as a colorless solid.

[3323]¹H-NMR (CDCl₃) δ: 7.37 (1H, dd, J=7.3, 4.9 Hz), 7.88 (1H, dt,J=7.3, 1.5 Hz), 8.14 (1H, s), 8.60 (1H, dd, J=4.9, 1.5 Hz), 8.85 (1H,s), 8.86 (1H, d, J=1.5 Hz).

Referential Example 2371-(tert-Butoxycarboyl)-4[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine

[3324] At room temperature, tetrakis(triphenylphosphine)palladium (470mg) was added to a solution of 4-bromo-2-methylpyridine (1.65 g) and(5-thiazolyl)trimethyltin (1.56 g) in benzene (80 ml), followed byheating under reflux for 14 hours. After allowed to cool down to roomtemperature, the reaction mixture was washed with a saturated aqueoussolution (100 ml) of sodium bicarbonate. The water layer was extractedwith ethyl acetate (50 ml). The organic layers were combined, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (methylene chloride:ethyl acetate=4:1→1:1), whereby2-methyl-4-(5-thiazolyl)pyridine was obtained as a colorless solid. Theresulting solid was dissolved in diethyl ether (30 ml) andtetrahydrofuran (30 ml), followed by the dropwise addition of n-butyllithium (a 1.52N hexane solution, 4.35 ml) at −78° C. After stirring for30 minutes, a carbon dioxide gas was blown into the react-ion mixture.Thirty minutes later, the reaction mixture was heated gradually to roomtemperature. The reaction mixture was concentrated, whereby the residueof lithium 5-(2-methylpyridin-4-yl)thiazole-2-carboxylate was obtainedas a colorless solid. To a solution of the resulting residue inN,N-dimethylformamide (40 ml) were added1-(tert-butoxycarbonyl)piperazine (1.30 g), 1-hydroxybenzotriazolemonohydrate (945 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.34 g) at room temperature. After stirring for 3 days,ethyl acetate (200 ml) and water (800 ml) were added to the reactionmixture to separate it into layers. The water layer was extracted withethyl acetate (2×100 ml). The organic layers were combined, washed withwater (800 ml) and a saturated aqueous solution (200 ml) of sodiumbicarbonate, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (methylene chloride:acetone=6:1),whereby the title compound (810 mg) was obtained as a colorlesstransparent viscous substance.

[3325]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.63 (3H, s), 3.57 (4H, t, J=4.9Hz), 3.79 (2H, br s), 4.43 (2H, br s), 7.30 (1H, d, J=4.9 Hz), 7.35 (1H,s), 8.14 (1H, s), 8.56 (1H, d, J=4.9 Hz). MS (FAB) m/z: 389 (M+H)⁺, 333(M+H-isobutene)⁺, 289 (M+HBoc)⁺.

Referential Example 2381-(tert-Butoxycarbonyl)-4-[5-(pyridin-4-yl)thiazol-2-yl]piperazine

[3326] Diethyl ether and a saturated aqueous solution of sodiumbicarbonate were added to 4-bromopyridine hydrochloride (3.76 g). Theorganic layer thus separated was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, whereby a diethyl ether solution of4-bromopyridine was obtained. To the resulting solution were added(5-thiazolyl)trimethyltin (4.00 g), benzene (150 ml) andtetrakis(triphenylphosphine)palladium (950 mg), followed by heatingunder reflux for 12 hours. After allowed to cool down to roomtemperature, the reaction mixture was added with a saturated aqueoussolution (100 ml) of sodium bicarbonate and ethyl acetate (50 ml). Thewater layer thus separated was extracted with ethyl acetate (2×50 ml)and methylene chloride (2×50 ml). The organic layers were combined,dried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (methylene chloride:ethyl acetate=5:1→2:1), whereby4-(5-thiazolyl)pyridine was obtained as a colorless, transparent oil.The resulting oil was dissolved in diethyl ether (80 ml), followed bythe dropwise addition of n-butyl lithium (a 1.52N hexane solution, 11.5ml) at −78° C. After stirring for 30 minutes, a carbon dioxide gas wasblown into the reaction mixture. Ten minutes later, the temperature wasincreased gradually to room temperature. The reaction mixture wasconcentrated, whereby the residue of lithium5-(pyridin-4-yl)thiazole-2-carboxylate was obtained as a colorlesssolid. To a solution of the resulting residue in N,N-dimethylformamide(50 ml) were added 1-(tert-butoxycarbonyl)piperazine (3.30 g),1-hydroxybenzotriazole monohydrate (2.40 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.40 g) atroom temperature. The resulting mixture was stirred for 3 days. Ethylacetate (200 ml) and water (2000 ml) were added to the reaction mixture.The water layer thus separated was extracted with ethyl acetate (2×200ml). The organic layers were combined, washed with water (1000 ml) and asaturated aqueous solution (400 ml) of sodium bicarbonate, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was reprecipitated in a methylenechloride—hexane system, whereby the title compound (3.00 g) was obtainedas pale brown powder.

[3327]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.57 (4H, t, J=5.6 Hz), 3.79 (2H,br s), 4.43 (2H, br s), 7.49 (2H, d, J=5.9 Hz), 8.17 (1H, s), 8.69 (2H,d, J=5.9 Hz).

[3328] MS (FAB) m/z: 375 (M+H)⁺, 319 (M+H-isobutene)⁺, 275 (M+HBoc)⁺.

Referential Example 239 5-(Pyridin-4-yl)thiazole

[3329] In a 3M aqueous solution of potassium carbonate, 4-bromopyridinehydrochloride (389 mg) was suspended, followed by extraction withdiethyl ether. The organic layer thus extracted with dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was dissolved in benzene (20 ml), followed bythe addition of 5-trimethylstannylthiazole (496 mg) (Synthesis, 198,757) and

[3330] tetrakis(triphenylphosphine)palladium (116 mg). In an argon gasstream, the resulting mixture was heated under reflux for 48 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by chromatography on a silica gel column (hexane:ethylacetate=3:1), whereby the title compound (293 mg) was obtained as a paleyellow oil.

[3331]¹H-NMR (CDCl₃) δ: 7.47 (2H, dd, J=4.9, 2.0 Hz), 8.27 (1H, s), 8.65(2H, dd, J=4.9, 2.0 Hz), 8.89 (1H, s).

[3332] MS (FAB) m/z: 163 (M+H)⁺.

Referential Example 240 Lithium 5-(pyridin-4-yl)thiazole-2-carboxylate

[3333] In diethyl ether (20 ml) was dissolved 5-(pyridin-4-yl)thiazole(290 mg), followed by the dropwise addition of an n-hexane solution(1.54M, 1.20 ml) of n-butyl lithium at −78° C. The resulting mixture wasstirred for 10 minutes. After a carbon dioxide gas was blown into thereaction mixture at −78° C. for 15 minutes, the reaction mixture washeated to room temperature. The reaction mixture was concentrated underreduced pressure, whereby the title compound (409 mg) was obtained as apale brown foam.

[3334]¹H-NMR (DMSO-d₆) δ: 7.66 (2H, d, J=5.4 Hz), 8.37 (1H, s), 8.59(2H, d, J=5.4 Hz).

[3335] MS (FD) m/z: 213 (M+Li⁺ H)⁺.

Referential Example 241 5-(Pyridin-2-yl)thiazole

[3336] In the same manner as in Referential Example 239, the titlecompound was obtained.

[3337]¹H-NMR (CDCl₃) δ: 7.22 (1H, t, J=5.9 Hz), 7.67-7.78 (3H, m), 8.34(1H, s), 8.60 (1H, d, J=4.9 Hz), 8.84 (1H, s).

[3338] MS (FAB) m/z: 163 (M+H)⁺.

Referential Example 242 Lithium 5-(pyridin-2-yl)thiazole-2-carboxylate

[3339] In the same manner as in Referential Example 240, the titlecompound was synthesized.

[3340]¹H-NMR (DMSO-d₆) δ: 7.31 (1H, m), 7.85 (1H, t, J=7.8 Hz), 7.94(1H, d, J=7.8 Hz), 8.36 (1H, s), 8.56 (1H, d, J=4.4 Hz).

Referential Example 243(5-tert-Butyldimethylsilyloxy-4-oxo-4H-pyran-2-yl)methyl Chloride

[3341] Kojic acid (5.00 g) was dissolved in methylene chloride (300 ml).To the resulting solution were added N,N-dimethylformamide (0.03 ml) andthionyl chloride (3.08 ml) under ice cooling, followed by stirringovernight at room temperature. The reaction mixture was concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran(600 ml). To the resulting solution were added triethylamine (19.51 ml),N,N-dimethylaminopyridine (0.20 g) and tert-butyldimethylsilyl chloride(7.95 g), followed by stirring at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure. Methylenechloride was added to the residue. The resulting mixture was washedsuccessively with a 0.3N aqueous solution of hydrochloric acid, asaturated aqueous solution of sodium bicarbonate and saturated aqueousNaCl solution, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=8:1),whereby the title compound (6.10 g) was obtained as a pale brown oil.

[3342]¹H-NMR (CDCl₃) δ: 0.23 (6H, s), 0.95 (9H, s), 4.30 (2H, s), 6.43(1H, s), 7.67 (1H, s).

[3343] MS (FAB) m/z: 275 (M+H)⁺.

Referential Example 244[(5-tert-Butyldimethylsilyloxy4-oxo-4H-pyran-2-yl)methyl]amine

[3344] In N,N-dimethylformamide (20 ml) was dissolved(5-tert-butyldimethylsilyloxy-4-oxo-4H-pyran-2-yl)methyl chloride (2.00g). Sodium azide (1.00 g) was added to the resulting solution and theresulting mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure. Ethyl acetatewas added to the residue, followed by washing once with water and thenonce with saturated aqueous NaCl solution. The organic layer thusextracted was dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The resulting residue wasdissolved in methanol (100 ml), followed by the addition of 10%palladium-carbon (50% wet w/w, 800 mg). The resulting mixture wasstirred overnight under a hydrogen gas stream of normal pressure. Thereaction mixture was subjected to Celite filtration, the filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography on a silica gel column (methylenechloride:methanol=100:3), whereby the title compound (290 mg) wasobtained as a colorless oil.

[3345]¹H-NMR (CDCl₃) δ: 0.23 (6H, s), 0.95 (9H, s), 3.68 (2H, s), 6.35(1H, s), 7.64 (1H, s).

[3346] MS (FAB) m/z: 256 (M+H)⁺.

Referential Example 2451-(tert-Butoxycarbonyl)-2-[N[(5-tert-butyldimethylsilyloxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[3347] In the same manner as in Referential Example 5, the titlecompound was obtained.

[3348]¹H-NMR (DMSO-d₆) δ: 0.15 (6H, s), 0.91 (9H, s), 1.30 (9H, br s),2.34-2.44 (1H, m), 2.56-2.71 (1H, m), 3.19-3.46 (1H, m), 3.55-3.68 (1H,m), 3.77-3.94 (1H, m), 4.03-4.32 (3H, m), 4.50-4.69 (1H, m), 6.22 (1H,br s), 7.00 (1H, s), 7.32 (1H, dd, J=8.8, 2.0 Hz), 7.49 (1H, d, J=8.8Hz), 7.79 (1H, d, J=2.0 Hz), 8.12 (1H, s), 8.66 (1H, br s), 12.43 (1H,s).

[3349] MS (FAB) m/z: 681 [(M+H)⁺, Cl³⁵], 683 [(M+H)⁺, Cl³⁷].

Referential Example 2461-(tert-Butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]piperazine

[3350] In tetrahydrofuran (10 ml) was dissolved1-(tert-butoxycarbonyl)-2-[N-[(5-tert-butyldimethylsilylox-4-oxo4H-pyran-2-yl)methyl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(570 mg), followed by the addition of a 1.0M tetrahydrofuran solution(8.37 ml) of tetrabutylammonium fluoride. The resulting mixture wasstirred at room temperature for 15 minutes. The reaction mixture wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (methylenechloride:methanol=100:3), whereby the title compound (475 mg) wasobtained as a pale yellow foam.

[3351]¹H-NMR (DMSO-d₆) δ: 1.31 (9H, br s), 2.30-2.86 (2H, m), 3.12-3.19(1H, m), 3.52-3.68 (1H, m), 3.80-3.94 (1H, m), 4.00-4.30 (3H, m),4.51-4.69 (1H, m), 6.23 (1H, br s), 7.00 (1H, s), 7.32 (1H, dd, J=8.8,2.0 Hz), 7.49 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 8.01 (1H, s),8.68 (1H, br s), 12.44 (1H, br s).

[3352] MS (FAB) m/z: 567 [(M+H)⁺, Cl³⁵], 569 [(M+H)⁺, Cl³⁷].

Referential Example 2472-[N-[(5-Acetoxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[3353] In acetonitrile (10 ml) was dissolved 1-(tert5butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]piperazine(411 mg), followed by the addition of acetic anhydride (0.075 ml) andtriethylamine (0.11 ml). The resulting mixture was stirred at roomtemperature for 15 minutes. The reaction mixture was concentrated underreduced pressure. Methylene chloride was added to the residue. Theresulting mixture was washed successively with 0.2N hydrochloric acid, asaturated aqueous solution of sodium bicarbonate and saturated aqueousNaCl solution. The organic layer was then dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(methylene chloride:methanol=50:5), whereby the title compound (256 mg)was obtained as a colorless foam.

[3354]¹H-NMR (DMSO-d₆) δ: 1.32 (9H, br s), 2.25 (3H, s), 2.31-2.70 (2H,m), 3.00 (1H, br s), 3.63 (1H, br s), 3.86 (1H, br s), 4.01-4.33 (3H,m), 4.52-4.70 (1H, m), 6.30 (1H, br s), 7.01 (1H, s), 7.32 (1H, dd,J=8.8, 2.0 Hz), 7.49 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 8.45(1H, s), 8.72 (1H, br s), 12.44 (1H, s).

[3355] MS (FAB) m/z: 609 [(M+H)⁺, Cl³⁵], 611 [(M+H)⁺, Cl³⁷].

Referential Example 2483-[N-[(5-Acetoxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-1-[(5-chloroindol-2-yl)sulfonyl]piperazineTrifluoroacetate

[3356] In methylene chloride (5 ml),2-[N-[(5-acetoxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-1-(tert-butoxycarbonyl)-4[(5-chloroindol-2-yl)sulfonyl]piperazinewas treated with trifluoroacetic acid (5 ml), followed by concentrationto dryness under reduced pressure, whereby the title compound (224 mg)was obtained.

[3357]¹H-NMR (DMSO-d₆) δ: 2.26 (3H, s), 2.57-2.72 (2H, m), 3.14-3.23(1H, m), 3.39 (1H, d, J=11.7 Hz), 3.65 (1H, d, J=11.7 Hz), 4.03-4.09(1H, m), 4.17-4.26 (1H, m), 4.34-4.42 (1H, m), 6.46 (1H, s), 7.12 (1H,s), 7.36 (1H, dd, J=8.8, 2.0 Hz), 7.52 (1H, d, J=8.8 Hz), 7.82 (1H, d,J=2.0 Hz), 8.50 (1H, s), 9.42 (1H, br s), 12.57 (1H, s).

[3358] MS (FAB) m/z: 509 [(M+H)⁺, Cl³⁵], 511 [(M+H)⁺, Cl³⁷].

Referential Example 249N-[[1-[(5-Chloroindol-2-yl)sulfonyl]piperazin-3-yl]acetyl]methanesulfonamideTrifluoroacetate

[3359] In tetrahydrofuran (5 ml) was dissolved1-(tert-butoxycarbonyl)-2-[(carboxy)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(772 mg), followed by the addition of carbonyldiimidazole (820 mg). Theresulting mixture was heated under reflux for 1 hour. After cooling toroom temperature, the reaction mixture was added with methanesulfonamide(322 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.50 ml), followed bystirring overnight. The reaction mixture was concentrated under reducedpressure. To the residue was added a 1N aqueous solution of hydrochloricacid. After removal of the supernatant, the precipitate was washed withwater and dried, whereby a colorless foam was obtained. The substancewas dissolved in methylene chloride (10 ml), followed by the addition oftrifluoroacetic acid (10 ml). The resulting mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was concentrated underreduced pressure. Diethyl ether was added to the residue and theprecipitate thus obtained was collected by filtration, whereby the titlecompound (863 mg) was obtained as a colorless solid.

[3360]¹H-NMR (DMSO-d₆) δ: 2.53-2.74 (3H, m), 3.25 (3H, s), 3.43-3.50(2H, m), 3.61-3.80 (4H, m), 7.10 (1H, s), 7.34 (1H, dd, J=8.8, 2.0 Hz),7.50 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=2.0 Hz), 12.58 (1H, s).

[3361] MS (FAB) m/z: 435 [(M+H)⁺, Cl³⁵], 437 [(M+H)⁺, Cl³⁷].

Referential Example 2501-(tert-Butoxycarbonyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-(ethoxycarbonyl)piperazine

[3362] In methylene chloride (200 ml) was dissolved2-ethoxycarbonylpiperazine acetate (2.08 g), followed by the addition oftriethylamine (3.63 ml). The resulting mixture was stirred overnight atroom temperature. To the reaction mixture, a methylene chloride solution(20 ml) of 6-chloroenzo[b]thiophene-2-sulfonyl chloride (2.00 g) wasslowly added dropwise over 2 hours. After stirring at room temperaturefor 30 minutes, di-tert-butyl dicarbonate (3.27 g) was added and theresulting mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure. Ethyl acetatewas added to the residue and the resulting mixture was washedsuccessively with 1N hydrochloric acid, a saturated aqueous solution ofsodium bicarbonate and saturated aqueous NaCl solution. The organiclayer thus extracted was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (hexane:ethylacetate=8:1), whereby the title compound (2.26 g) was obtained as a paleyellow foam.

[3363]¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.3 Hz), 1.36-1.49 (9H, m), 2.52(1H, td, J=11.7, 3.4 Hz), 2.66-2.77 (1H, m), 3.20-3.42 (1H, m),3.68-3.82 (1H, m), 3.87-4.08 (1H, m), 4.17-4.40 (1H, m), 4.68 (1/2H, brs), 4.87 (1/2H, br s), 7.43 (1H, dd, J=8.3, 2.0 Hz), 7.77 (1H, s), 7.82(1H, d, J=8.3 Hz), 7.86 (1H, d, J=2.0 Hz).

[3364] MS (FAB) m/z: 489 [(M+H)⁺, Cl³⁵], 491 [(M+H)⁺, Cl³⁷].

Referential Example 2511-(tert-Butoxycarbonyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine-2-carboxylicAcid

[3365] In tetrahydrofuran (10 ml) was dissolved1-(tert-butoxycarbonyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-(ethoxycarbonyl)piperazine(2.25 g), followed by the addition of ethanol (20 ml) and a 3N aqueoussolution (3 ml) of sodium hydroxide. The resulting mixture was stirredat room temperature for 3 hours. The reaction mixture was concentratedunder reduced pressure. The residue was adjusted to have pH of 1 to 2 bythe addition of a 1N aqueous solution of hydrochloric acid. Ethylacetate was then added and the organic layer was collected. The organiclayer was dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The solid thus precipitated wascollected by filtration, whereby the title compound (2.17 g) wasobtained as a colorless solid.

[3366]¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.54 (1H, dt, J=11.7, 3.4 Hz),2.69-2.79 (1H, m), 3.20-3.44 (1H, m), 3.70-3.84 (1H, m), 3.89-4.12 (1H,m), 4.30-4.41 (1H, m), 4.78 (1/2H, br s), 4.98 (1/2H, br s), 7.45 (1H,dd, J=8.3, 2.0 Hz), 7.79 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.88 (1H, d,J=2.0 Hz).

[3367] MS (FAB) m/z: 461 [(M+H)⁺, Cl³⁵], 463 [(M+H)⁺, Cl³⁷].

Referential Example 2521-[(6-Chlorobenzo[b]thine-2-yl)sulfonyl]-3-[(N-methyl)carbamoyl]piperazineHydrochloride

[3368] In N,N-dimethylformamide (50 ml) were dissolved1-(tert-butoxycarbonyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine-2-carboxylicacid (691 mg), N-methylamine hydrochloride (111 mg),1-hyroxybenzotriazole monohydrate (230 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (345 mg).Triethylamine (0.23 ml) was added to the resulting solution, followed bystirring overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue, followed by washing with water. The organic layer was driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by chromatography on a silicagel column (methylene chloride:methanol=100:1), whereby a pale yellowfoam was obtained. The resulting foam was dissolved in a saturatedhydrochloric acid/ethanol solution (10 ml) and the resulting solutionwas concentrated under reduced pressure. The solid thus precipitated wascollected by filtration while being washed with ethyl acetate, wherebythe title compound (468 mg) was obtained as a colorless solid.

[3369]¹H-NMR (DMSO-d₆) δ: 2.67 (3H, d, J=4.4 Hz), 2.77 (1H, t, J=11.2Hz), 2.87 (1H, t, J=11.2 Hz), 3.15-3.25 (1H, m), 3.32-3.40 (1H, m), 3.70(1H, d, 12.7 Hz), 3.98-4.03 (1H, m), 4.07-4.15 (1H, m), 7.62 (1H, dd,J=8.8, 2.0 Hz), 8.11 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.40 (1H, d, J=2.0Hz), 8.80 (1H, d, J=4.4 Hz).

[3370] MS (FAB) m/z: 374 ((M+H)⁺, Cl³⁵], 376 [(M+H)⁺, Cl³⁷].

Referential Example 253 Ethyl (piperazin-1-yl)acetate Hydrochloride

[3371] In N,N-dimethylformamide (50 ml) was dissolved1-(tert-butoxycarbonyl)piperazine (942 mg). After the addition oftriethylamine (1.40 ml), ethyl bromoacetate (1.13 ml) was added,followed by stirring overnight at room temperature. The reaction mixturewas concentrated under reduced pressure. Ethyl acetate was added to theresidue and the mixture was washed with water. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by chromatography on a silicagel column (hexane:ethyl acetate=3:1), whereby a colorless foam wasobtained. The resulting substance was dissolved in a saturatedhydrochloric acid—ethanol solution (10 ml) and the resulting solutionwas concentrated under reduced pressure. The solid thus precipitated wascollected by filtration while being washed with ethyl acetate, wherebythe title compound (841 mg) was obtained as a colorless solid.

[3372]¹H-NMR (DMSO-d₆) δ: 1.24 (3H, t, J=7.3 Hz), 3.36 (8H, br s), 4.08(2H, br s), 4.18 (2H, q, J=7.3 Hz), 9.73 (2H, br s).

[3373] MS (FAB) m/z: 173 (M+H)⁺.

[3374] In the same manner as in Referential Example 252, the compoundsshown in Referential Examples 254 to 255 were synthesized.

Referential Example 254 Ethyl[4-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]piperazin-1-yl]acetateHydrochloride

[3375]¹H-NMR (DMSO-d₆) δ: 1.26 (3H, t, J=7.3 Hz), 2.51-2.78 (1H, m),2.90-4.32 (17H, m), 4.79 (1H, br s), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.90(1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz), 8.29 (1H, s), 8.32 (1H, d,J=8.8 Hz), 8.63 (1H, s), 8.90 (1H, br s).

[3376] MS (FAB) m/z: 509 [(M+H)⁺, Cl³⁵], 511 ((M+H)⁺, Cl³⁷].

Referential Example 2555-[[[[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]amino]methyl]tetrazoleTrifluoroacetate

[3377]¹H-NMR (DMSO-d₆) δ: 2.53-2.68 (2H, m), 3.15-3.23 (1H, m),3.30-3.37 (1H, m), 3.68-3.76 (1H, m), 4.12-4.20 (2H, m), 4.65-4.68 (2H,m), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.86 (1H, dd, J=8.8, 2.0 Hz), 8.26(1H, d, J=8.8 Hz), 8.30-8.34 (2H, m), 8.56 (1H, s), 9.51-9.59 (1H, m).

[3378] MS (FAB) m/z: 435 [(M+H)⁺, Cl³⁵], 437 [(M+H)⁺, Cl³⁷].

Referential Example 256[1-(tert-Butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-2-yl]aceticHydrazinamide

[3379] In tetrahydrofuran (20 ml) was dissolved1-[1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-2-yl]aceticacid (1.11 g). To the resulting solution, N-methylmorpholine (0.26 ml)and isobutyl chloroformate (0.31 ml) were successively added dropwise at−20° C. After stirring at −20° C. for 10 minutes, hydrazine hydrate (690ml) was added. The reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate. The resultingsolution was washed with a 1N aqueous solution of hydrochloric acid,saturated sodium bicarbonate and saturated aqueous NaCl solution, eachonce. The organic layer was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column [methylenechloride:methanol=100:0 to 100:1], whereby the title compound (513 mg)was obtained as a colorless foam.

[3380]¹H-NMR (DMSO-d₆) δ: 1.31 (9H, s), 2.14-2.38 (3H, m), 3.00-3.12(1H, m), 3.57-3.68 (2H, m), 3.83-3.90 (1H, m), 4.16 (2H, br s), 4.51(1H, br s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.78 (1H, d, J=8.8 Hz), 8.15(1H, d, J=8.8 Hz), 8.23 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.47 (1H, s),9.08 (1H, s).

[3381] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

Referential Example 2572-[[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]methyl]-4,5-dihydro-5-oxo-1,3,4-oxadiazoleTrifluoroacetate

[3382] In tetrahydrofuran (2 ml) was dissolved[1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-2-yl]acetichydrazinamide (505 mg), followed by the addition of carbonyl diimidazole(102 mg) and triethylamine (0.14 ml). The resulting mixture was stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure. Methylene chloride was added to theresidue. The resulting mixture was washed with a 1N aqueous solution ofhydrochloric acid, water and saturated aqueous NaCl solution, each once.The organic layer so extracted was dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. The residuewas purified by chromatography on a silica gel column (methylenechloride:methanol=100:0 to 100:1), whereby a colorless foam wasobtained. The resulting substance was dissolved in methylene chloride (2ml), followed by the addition of trifluoroacetic acid (5 ml). Afterstirring at room temperature for 1 minute, the reaction mixture wasconcentrated under reduced pressure. The residue was washed with diethylether. The precipitate thus obtained was collected by filtration,whereby the title compound (412 mg) was obtained as a colorless foam.

[3383]¹H-NMR (DMSO-d₆) δ: 2.60-2.79 (2H, m), 2.85 (1H, dd, J=16.1, 6.8Hz), 3.03 (1H, dd, J=16.1, 6.8 Hz), 3.20 (1H, d, J=10.2 Hz), 3.43 (1H,d, J=12.7 Hz), 3.71 (1H, d, J=11.2 Hz), 3.90 (1H, d, J=11.2 Hz), 7.74(1H, dd, J=8.8, 2.0 Hz), 7.86 (1H, dd, J=8.8, 2.0 Hz) 8.21 (1H, d, J=8.8Hz), 8.27 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.55 (1H, s), 12.30 (1H, s).

[3384] MS (FAB) m/z: 409 [(M+H)⁺, Cl³⁵], 411 [(M+H)⁺, Cl³⁷].

Referential Example 2581-(tert-Butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxylethyl)piperazine

[3385] In tetrahydrofuran (100 ml) was dissolved1-[1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-2-yl]aceticacid (2.00 g). The resulting solution was successively added dropwisewith N-methylmorpholine (0.51 ml) and isobutyl chloroformate (0.64 ml)at −20° C. After stirring at −20° C. for 10 minutes, sodium borohydride(483 mg) and methanol (20 ml) were added successively to the reactionmixture. The resulting mixture was stirred for 10 minutes. Afterconcentration under reduced pressure, the residue was dissolved in ethylacetate. The resulting solution was washed with a 1N aqueous solution ofhydrochloric acid, a saturated aqueous solution of sodium bicarbonateand saturated aqueous NaCl solution, each once. The organic layer wasdried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (methylene chloride:methanol=100:0 to 100:3), wherebythe title compound (1.75 g) was obtained as a colorless foam. 2.18 (1H,m), 2.33 (1H, dt, J=11.7, 3.4 Hz), 2.50-2.59 (1H, m), 3.07 (1H, dt,J=3.4, 12.7 Hz), 3.25-3.42 (1H, m), 3.60-3.78 (3H, m), 3.90-3.98 (1H,m), 4.37-4.44 (1H, m), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.74 (1H, dd,J=8.8, 2.0 Hz), 7.88-7.95 (3H, m), 8.29 (1H, s).

[3386] MS (FAB) m/z: 455 [(M+H)⁺, Cl³⁵], 457 [(M+H)⁺, Cl³⁷].

Referential Example 2592-(2-Bromoethyl)-1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3387] In methylene chloride (50 ml) was dissolved1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxylethyl)piperazine(1.00 g), followed by the addition of carbon tetrabromide (1.46 g) andtriphenylphosphine (1.15 g). The resulting mixture was stirred at roomtemperature for 30 minutes. After the addition of a saturated aqueoussolution of sodium sulfite, the organic layer was collected from themixture. The organic layer was dried over anhydrous sodium sulfate andthen distilled under reduced pressure to remove the solvent. The residuewas purified by chromatography on a silica gel column [hexane:ethylacetate=10:1 to 6:1], whereby the title compound (990 mg) was obtainedas a colorless foam.

[3388]¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.20-2.41 (3H, m), 2.44 (1H, dd,J=12.2, 3.9 Hz), 3.04-3.15 (1H, m), 3.43 (1H, br s), 3.68 (1H, d, J=12.2Hz), 3.77 (1H, d, J=10.7 Hz), 3.95-4.15 (1H, m), 4.46 (1H, br s), 7.58(1H, dd, J=8.8, 2.0 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.87-7.94 (3H,m), 8.29 (1H, s).

[3389] MS (FAB) m/z: 518 [(M+H)⁺, Cl³⁵], 520 [(M+H)⁺, Cl³⁷].

Referential Example 2601-(tert-Butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-cyanoethyl)piperazine

[3390] In N,N-dimethylformamide (20 ml) was dissolved2-(2bromoethyl)-1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(980 mg), followed by the addition of sodium cyanide (102 mg). Theresulting mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure. Ethyl acetatewas added to the residue and the resulting mixture was washed with waterand saturated aqueous NaCl solution, each once. The organic layer thusextracted was dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent, whereby the title compound (842mg) was obtained as a colorless foam.

[3391]¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.92-2.03 (1H, m), 2.21-2.44 (4H,m), 2.48 (1H, dd, J=11.7, 3.9 Hz), 3.13 (1H, br s), 3.68 (1H, d, J=11.7Hz), 3.77 (1H, d, J=11.7 Hz), 4.09 (1H, br s), 4.38 (1H, br s), 7.58(1H, dd, J=8.8, 2.0 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.88-7.95 (3H,m), 8.29 (1H, s).

[3392] MS (FAB) m/z: 464 [(M+H)⁺, Cl³⁵], 466 [(M+H)⁺, Cl³⁷].

Referential Example 2615-[2-[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]ethyl]tetrazole

[3393] In N,N-dimethylformamide (1.5 ml) was dissolved1(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-cyanoethyl)piperazine(529 mg), followed by the addition of ammonium chloride (588 mg) andsodium azide (741 mg). The resulting mixture was stirred under heatingat 100° C. The reaction mixture was concentrated under reduced pressure.Ethyl acetate was added to the residue and the resulting mixture waswashed with water and saturated aqueous NaCl solution, each once. Theorganic layer thus extracted was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (methylenechloride:methanol=50:1), whereby a colorless foam was obtained. Theresulting substance was dissolved in methylene chloride (5 ml), followedby the addition of trifluoroacetic acid (5 ml). The mixture was stirredat room temperature for 1 minutes. The reaction mixture was concentratedunder reduced pressure. The precipitate thus obtained was washed withdiethyl ether and collected by filtration, whereby the title compound(141 mg) was obtained as a colorless solid.

[3394]¹H-NMR (DMSO-d₆) δ: 1.95-2.08 (2H, m), 2.45-2.70 (2H, m),2.98-3.22 (3H, m), 3.35-3.51 (2H, m), 3.62-3.88 (2H, m), 7.75 (1H, d,J=8.8 Hz), 7.88 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.27 (1H, s),8.29 (1H, d, J=8.8 Hz), 8.56 (1H, s).

[3395] MS (FAB) m/z: 407 [(M+H)⁺, Cl³⁵], 409 [(M+H)⁺, Cl³⁷].

[3396] In the same manner as in Example A-4, the compounds shown inReferential Examples 262 and 263 were obtained.

Referential Example 2621-(tert-Butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N-methylcabamoyl)methyl)piperazine

[3397]¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 2.34-2.45 (1H, br), 2.50-2.63 (1H,br), 2.63-2.80 (2H, br), 2.83 (3H, d, J=4.6 Hz), 2.98-3.10 (1H, m),3.65-4.15 (3H, br), 4.62 (1H, br s), 6.05-6.25 (1H, br), 6.97 (1H, d,J=1.7 Hz), 7.29 (1H, dd, J=8.8, 1.7 Hz), 7.40 (1H, d, J=8.8 Hz), 7.66(1H, d, J=1.7 Hz).

[3398] MS (FAB) m/z: 471 [(M+H)⁺, Cl³⁵], 473 [(M+H)⁺, Cl³⁷].

Referential Example 2631-(tert-Butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[N-(tetrahydrofurfuryl)carbamoyl]methyl]piperazine

[3399]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.50-1.70 (1H, m), 1.85-2.10 (3H,m), 2.25-2.35 (1H, br), 2.50-2.85 (3H, br), 2.89-3.20 (2H, m), 3.25-3.50(1H, br), 3.55-4.17 (6H, m), 4.57 (1H, br s), 6.29 (1H, br s), 6.90-6.97(1H, m), 7.21-7.38 (2H, m), 7.60-7.68 (1H, m).

[3400] MS (FAB) m/z: 541 [(M+H)⁺, Cl³⁵], 543 [(M+H)⁺, Cl³⁷].

Referential Example 264 1,4-Dibenzyl-2-(2-formylmethyl)piperazine

[3401] In methylene chloride (30 mL) was dissolved1,4-dibenzyl-2-(2-hydroxyethyl)piperazine (620 mg), followed by theaddition of 4-methylmorpholine N-oxide (281 mg) and tetrapropylammoniumperruthenate (141 mg) under ice cooling. Ten minutes later, theresulting mixture was allowed to rise back to room temperature, followedby stirring. After 18 hours, the solvent was distilled off under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (ethyl acetate:hexane=1:1), whereby the title compound (360 mg)was obtained as a colorless oil.

[3402]¹H-NMR (CDCl₃) δ: 2.33-2.82 (8H, m), 3.13 (1H, brs), 3.34 (1H, d,J=13.2 Hz), 3.48 (2H, ABq, J=13.2 Hz), 3.81 (1H, d, J=13.2 Hz), 7.29(10H, m), 9.81 (1H, s).

[3403] MS (FAB) m/z: 309 [(M+H)⁺].

Referential Example 2651,4-Dibenzyl-2-[2-(1-piperidinyl)ethyl]piperazine

[3404] In methanol (10 mL) were dissolved1,4-dibenzyl-2-(formylmethyl)piperazine (600 mg) and piperidine (200mg). After stirring for 30 minutes, the solvent was concentrated underreduced pressure. The concentrate was dissolved in methanol (10 mL),followed by the addition of sodium borohydride (147 mg). The resultingmixture was stirred. Five hours later, the solvent was distilled offunder reduced pressure. Chloroform was added to the residue and themixture was washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica ael column (methylenechloride:methanol=10:1→5:1), whereby the title compound (640 mg) wasobtained as a colorless oil.

[3405]¹H-NMR (CDCl₃) 6:1.42 (2H, m), 1.57 (4H, m), 1.85 (2H, m),2.22-2.70 (13H, m), 3.22 (1H, d, J=13.5 Hz), 3.46 (2H, Abq, J=13.0 Hz),3.99 (1H, d, J=13.2 Hz), 7.30 (10H, m).

[3406] MS (FAB) m/z: 378 [(M+H)⁺].

Referential Example 2661-[(5-Chloro-lphenylsulfonylindol-2-yl)sulfonyl]-3-[2-(1-piperidinyl)ethyl]piperazine

[3407] To 1,4-dibenzyl-2-[2-(1-piperidinyl)ethyl]piperazine (740 mg) wasadded 10% palladium-carbon (100 mg). The resulting mixture was dissolvedin acetic acid (5.0 ml), followed by stirring under a hydrogen gasstream of 1 atmospheric pressure. Twenty hours later, the palladium wasfiltered off and the filtrate was concentrated under reduced pressure.The resulting residue was dissolved in methylene chloride (10 mL),followed by the addition of triethylamine (595 mg). To the resultingmixture, 5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (765 mg) wasadded dropwise over 90 minutes and stirring was continued at roomtemperature. After 19 hours, chloroform was added and the resultingmixture was washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was dried over anhydrous magnesiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column (methylenechloride:methanol:isopropylamine=500:75:1), whereby the title compound(335 mg) was obtained as a colorless oil.

[3408]¹H-NMR (CDCl₃) δ: 1.46-1.86 (8H, m), 2.50-3.19 (11H, m), 3.74 (2H,m), 7.13-7.57 (6H, m), 7.99 (1H, d, J=9.5 Hz), 8.02 (1H, d, J=8.3 Hz),8.22 (1H, d, J=9.0 Hz).

[3409] MS (FAB) m/z: 551 [(M+H)⁺].

Referential Example 2671,4-Dibenzyl-2-[2-(2-methoxyethyl)aminoethyl]piperazine

[3410] In the same manner as in Referential Example 265, the titlecompound was obtained.

[3411]¹H-NMR (CDCl₃) δ: 1.84 (2H, m), 2.22 (3H, m), 2.51-2.81 (8H, m),3.23 (1H, d, J=14.4 Hz), 3.35 (3H, s), 3.41-3.52 (4H, m), 4.02 (1H, d,J=13.2 Hz), 7.30 (10H, m).

[3412] MS (FAB) m/z: 368 (M+H)⁺.

Referential Example 2682-[2-[N-(tert-Butoxycarbonyl)-(2-methoxyethyl)amino]ethyl]-1,4-dibenzyl-piperazine

[3413] To 1,4-dibenzyl-2-[2-[(2-methoxyethyl)amino]ethyl]piperazine (540mg) was added ditert-butyl dicarbonate (353 mg). The resulting mixturewas dissolved in methylene chloride (10 mL), followed by the addition oftriethylamine (223 mg). After stirring for 3 days, the reaction wasterminate. The solvent was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (methylenechloride:methanol=100:1), whereby the title compound (610 mg) wasobtained as a colorless oil.

[3414]¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 1.87 (2H, m), 2.21 (3H, m), 2.53(2H, m), 2.68 (2H, m), 3.22-3.52 (9H, m), 3.29 (3H, s), 4.03 (1H, d,J=13.5 Hz), 7.30 (10H, m).

[3415] MS (FAB) m/z: 468 [(M+H)⁺].

Referential Example 2693-[2-[N-(tert-Butoxycarbonyl)-N-(2-methoxyethyl)amino]ethyl]-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]piperazine

[3416] To2-[2-[N-(tert-butoxycarbonyl)-2-methoxyethyl)amino]ethyl]-1,4-dibenzyl-piperazine(610 mg) was added 10% palladium-carbon (100 mg). The resulting mixturewas dissolved in methanol (10 mL), followed by stirring under a hydrogengas stream of 1 atmospheric pressure. After 3 days, palladium wasfiltered off and the solvent was concentrated under reduced pressure.The residue was dissolved in methylene chloride (10 mL), followed by theaddition of triethylamine (390 mg). To the resulting mixture,5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (503 mg) was addeddropwise over 30 minutes. Stirring was continued at room temperature.After 22 hours, chloroform was added and the resulting mixture waswashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (methylenechloride:methanol=25:1), whereby the title compound (490 mg) wasobtained as a colorless oil.

[3417]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.46-3.76 (15H, m), 3.31 (3H, s),7.21-7.56 (6H, m), 8.01 (2H, d, J=7.4 Hz), 8.22 (1H, d, J=9.1 Hz).

[3418] MS (FAB) m/z: 641 [(M+H)⁺].

Referential Example 270 Ethyl5-hydrazino-3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylate

[3419] At room temperature, ethyl2,5-dihydro-S-oxo-3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylate (246 mg)was added to phosphorus oxychloride (3 ml) in one portion, followed bystirring for 5 minutes. The reaction mixture was then heated to 90° C.and stirred for 6 hours. After completion of the reaction, the solventwas distilled off. The residue was successively added with ice water, asaturated aqueous solution of sodium bicarbonate and diethyl ether. Theorganic layer thus separated was dried over anhydrous magnesium sulfate.The desiccant was removed by filtration. To the filtrate was addeddioxane (50 ml), followed by cooling to 0° C. Hydrazine monohydrate (146μl) was added and the mixture was stirred for 1 minute. The solvent wasdistilled off and water was added to the residue. The pale yellow powderthus precipitated was collected by filtration and dried, whereby thetitle compound (52 mg) was obtained.

[3420]¹H-NMR (DMSO-d₆) δ: 1.36 (3H, t, J=7.3 Hz), 4.41 (2H, q, J=7.3Hz), 5.32 (2H, br), 8.35 (2H, br s), 8.81 (2H, d, J=6.4 Hz), 9.61 (1H,br).

[3421] MS (FAB) m/z: 261 (M+H)⁺.

Referential Example 271 Ethyl3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylate

[3422] In ethanol (5 ml) was suspended ethyl5-hydrazino-3(pyridin-4-yl)-1,2,4-triazine-6-carboxylate (50 mg). To theresulting suspension, mercury (II) oxide (98 mg) was added and theresulting mixture was heated under reflux for 9 hours. After completionof the reaction, the insoluble matter was removed through Celitefiltration. The filtrate was concentrated and the concentrate wasseparated into layers by the addition of ethyl acetate and water. Theorganic layer thus obtained was dried over anhydrous magnesium sulfate.The filtrate was concentrated, whereby a crudely purified product of thetitle compound (23 mg, pale yellow powder) was obtained.

[3423]¹H-NMR (CDCl₃) δ: 1.52 (3H, t, J=7.3 Hz), 4.61 (2H, q, J=7.3 Hz),8.45 (2H, d, J=6.4 Hz), 8.89 (2H, d, J=6.4 Hz), 9.33 (1H, s).

[3424] MS (FAB) m/z: 231 (M+H)⁺.

Referential Example 272 Ethyl bromo(pyridin-4-yl)aretate Hydrochloride

[3425] At room temperature, ethyl pyridin-4-ylacetate (5.00 g) wasdissolved in acetic acid (100 ml), followed by the addition of asaturated acetic acid solution (50 ml) of hydrogen bromide. Bromine(1.56 ml) was slowly added dropwise to the resulting mixture. Afterstirring at room temperature for 1 hour, the reaction mixture wasconcentrated. Acetone was added to the concentrate. Colorless powder wascollected by filtration, followed by drying. The resulting powder wasextracted with ethyl acetate and a saturated aqueous solution of sodiumbicarbonate. The organic layer was dried over anhydrous sodium sulfateand the filtrate was concentrated. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=1:1),followed by the addition of 1N hydrochloric acid (in ethanol) to makethe mixture acidic. The acidified solution was concentrated, whereby thetitle compound (colorless powder, 2.68 g) was obtained.

[3426]¹H-NMR (DMSO-d₆) δ: 1.20 (3H, t, J=7.3 Hz), 4.15-4.30 (2H, m),6.28-6.29 (1H, m), 8.01 (2H, d, J=6.4 Hz), 8.92 (2H, d, J=6.4 Hz).

[3427] MS (FAB) m/z: 244 [(M+H)⁺, Br⁷⁹], 246 [(M+H)⁺, Br⁸¹].

Referential Example 273 Ethyl (pyridin-4-yl)glyoxylate Hydrate

[3428] Ethyl bromo(pyridin-4-yl)acetate hydrochloride (2.05 temperature,followed by the addition of sodium azide (1.43 g). The resulting mixturewas stirred for 30 minutes. After the addition of water and stirring,the insoluble matter was filtered off and the filtrate was concentrated.The residue was extracted with diethyl ether and saturated aqueous NaClsolution. The organic layer thus obtained was dried over anhydrousmagnesium sulfate. The filtrate was concentrated and the residue wascrystallized from methylene chloride, whereby the title compound (yellowpowder, 300 mg) was obtained.

[3429]¹H-NMR (DMSO-d₆) δ: 1.10 (3H, t, J=7.3 Hz), 4.05 (2H, d, J=7.3Hz), 7.22 (2H, s), 7.48 (2H, d, J=5.9 Hz), 8.56 (2H, d, J=6.4 Hz).

[3430] MS (EI) m/z: 198 (M+18)⁺, 179 M⁺.

Referential Example 274 Ethyl2,5-dihydro-5-oxo-6(pyridin-4-yl)-1,2,4-triazine-3-carboxylate

[3431] Ethyl thiooxamate (172 mg) was suspended in ethanol (5 ml) at 0°C., followed by the addition of hydrazine monohydrate (63 μl). While theresulting gas was suctioned, the resulting mixture was stirred for 30minutes. Ethyl (pyridin-4-yl)glyoxylate hydrate (254 mg) was added tothe reaction mixture and the mixture was stirred at room temperature for30 minutes. After heating under reflux for 4 hours, the reaction mixturewas concentrated. The yellow powder thus precipitated was collected byfiltration and dried whereby the title compound (140 mg) was obtained.

[3432]¹H-NMR (DMSO-d₆) δ: 1.36 (3H, t, J=7.3 Hz), 4.42 (2H, d, J=7.3Hz), 8.08 (2H, d, J=4.9 Hz), 8.74 (2H, br s).

[3433] MS (FAB) m/z: 247 (M+H)⁺.

Referential Example 2752,5-Dihydro-5-oxo-6-(pyridin-4-yl)-1,2,4-triazine-3-carboxylic Acid

[3434] In the same manner as in Referential Example 11, the titlecompound was synthesized.

[3435]¹H-NMR (DMSO-d₆ with one drop of TFA) δ: 8.65 (2H, d, J=5.4 Hz),8.88 (1H, s), 9.00 (2H, d, J=5.4 Hz).

Referential Example 2761-(4-Bromophenylsulfonyl)-4-(tert-butoxycarbonyl)piperazine

[3436] Diisopropylethylamine (4.00 ml) was added to a solution of4-bromobenzenesulfonyl chloride (3.00 g) and1(tert-butoxycarbonyl)piperazine (2.40 g) in methylene chloride (50 ml)at room temperature. After stirring at room temperature for 30 minutes,the reaction mixture was concentrated under reduced pressure. Theresidue thus obtained was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=4:1→1:1), followed by reprecipitation in ahexane—methylene chloride system, whereby the title compound (4.47 g)was obtained as a colorless solid.

[3437]¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 2.97 (4H, t, J=5.1 Hz), 3.51 (4H,t, J=5.1 Hz), 7.61 (2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.8 Hz).

[3438] MS (FAB) m/z: 405 [(M+H)⁺, Br⁷⁹], 407 [(M+H)⁺, Br⁸¹], 349[(M+H-isobutene)⁺, Br⁷⁹], 351 [(M+H-isobutene)⁺, Br⁸¹], 305[(M+H-isobutene-CO₂)⁺, Br⁷⁹], 307 [(M+H-isobutene-CO²)⁺, Br⁸¹].

Referential Example 2771-(tert-Butoxycarbonyl)-4-[4-(pyridin-4-yl)benzenesulfonyl]piperazine

[3439] To a solution of1-(4-bromobenzenesulfonyl)-4-(tert-butoxycarbonyl)piperazine (1.00 g) intetrahydrofuran (50 ml) were added diethyl(pyridin-4-yl)boron (470 mg),tetrabutylammonium bromide (480 mg), potassium hydroxide (625 mg),tetrakistriphenylphosphine palladium (285 mg) and water (800 μl) at roomtemperature. The resulting mixture was heated under reflux for 1 hour.After allowed to cool down, the reaction mixture was added with ethylacetate (50 ml) and water (100 ml). The water layer thus separated wasextracted with ethyl acetate (50 ml). The organic layers were combined,washed with saturated aqueous NaCl solution (50 ml), dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (methylene chloride:ethyl acetate=1:1), whereby the titlecompound (540 mg) was obtained as a colorless transparent viscoussubstance.

[3440]¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 3.04 (4H, t, J=5.0 Hz), 3.54 (4H,t, J=5.0 Hz), 7.52 (2H, d, J=5.9 Hz), 7.79 (2H, d, J=8.8 Hz), 7.87 (2H,d, J=8.8 Hz), 8.74 (2H, d, J=5.9 Hz).

Referential Example 2781-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine

[3441] To a methylene chloride solution (30 ml) of2-(2-methylpropyl)piperazine hydrochloride (353 mg) were added6-chlorobenzo[b]thiophene-2-sulfonyl chloride (438 mg) and triethylamine(498 mg). The resulting mixture was stirred at room temperature for 3hours. Distilled water and methylene chloride were added. The waterlayer thus obtained was extracted three times with methylene chloride.The organic layers were combined, dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. The residuewas subjected to chromatography on a silica gel column (methanolmethylene chloride=1:100), whereby the title compound (363 mg) wasobtained as a pale yellow oil.

[3442]¹H-NMR (CDCl₃) δ: 0.78-0.94 (0.5H, m), 1.16-1.34 (0.5H, m),1.40-1.54 (1H, m), 1.70 (3H, s), 1.71 (3H, s), 2.24 (1H, t, J=11.2 Hz),2.55 (1H, dt, J=3.4, 11.2 Hz), 2.92-3.08 (2H, m), 3.52-3.62 (2H, m),3.65-3.74 (1H, m), 4.92 (1H, d, J=8.3 Hz), 7.43 (1H, dd, J=8.8, 2.0 Hz),7.74 (1H, s), 7.81 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=2.0 Hz).

[3443] MS (FAB) m/z: 383 [(M+H)⁺, Cl³⁵], 385 [(M+H)⁺, Cl³⁷].

Referential Example 2791-[(5-Bromopyrimidin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thiophen-2-yl)sulfonyl]-2-(2-methylpropyl)piperazine

[3444] To an N,N-dimethylformamide solution (60 ml) of1-[(6-chlorobenzo[b]thiophen-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine(2.55 mg) were added bromo-trispyrrolidino-phosphoniumhexafluorophosphate (607 mg, 1.17 mmol),(4-bromopyrimidin-2-yl)carboxylic acid (237 mg) and triethylamine (118mg), followed by stirring at room temperature for 13 hours. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure. Distilled water and methylene chloride were added to theresidue. The water layer thus obtained was extracted three times withmethylene chloride. The organic layers were combined and washed withdistilled water. After drying over anhydrous magnesium sulfate, thesolvent was distilled under off under reduced pressure. The residue wassubjected to chromatography on a silica gel column (methanol:methylenechloride=1:100), followed by crystallization from ethyl acetate—diethylether, whereby the title compound (326 mg) was obtained as browncrystals.

[3445]¹H-NMR (CDCl₃) δ: 0.70-1.07 (1H, m), 1.20-1.32 (1H, m), 1.64-1.76(1H, m), 1.79 (3H, s), 1.83 (3H, s), 2.56-2.97 (2H, m), 3.36-3.66 (2H,m), 3.70-3.81 (1H, m), 3.85-3.94 (0.5H, m), 4.57-5.03 (0.5H, m), 7.46(1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, s), 7.82 (1H, d, J=8.8 Hz), 7.88 (1H,br), 8.58-8.72 (2H, m).

[3446] MS (FAB) m/z=555 (M⁺), 557 [(M+2)⁺], 559 [(M+4)^(+].)

Referential Example 280 1-(tert-Butoxycarbonyl)-3,3-dimethylpiperazine

[3447] To a methylene chloride solution (5.0 ml) of2,2-dimethylpiperazine (460 mg, 4.03 mmol) (J. Med. Chem., 1995, 38,4389) was added di-tert-butyl dicarbonate (780 μl). The resultingmixture was stirred for 3 hours. The reaction mixture was diluted withmethylene chloride and then added with saturated aqueous NaCl solutionto separate into two layers. The water layer thus obtained was extractedwith methylene chloride. The extract was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crudely purifiedproduct was purified by chromatography on a silica gel column (methylenechloride:methanol=10:1), whereby the title compound (360 mg) wasobtained as a colorless oil.

[3448]¹H-NMR (CDCl₃) δ: 1.19 (6H, s), 1.46 (9H, s), 2.93 (2H, t, J=4.9Hz), 3.23 (2H, s), 3.42-3.48 (2H, br), 3.95-4.01 (1H, s).

Referential Example 2814-(tert-Butoxycarbonyl)-1-[(6-chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazine

[3449] To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperazine(125 mg) in methylene chloride (3.0 ml) were added triethylamine (90 ml)and 6-chloronaphthalene-2-sulfonyl chloride (167 mg). The resultingmixture was stirred at room temperature for 84 hours. The reactionmixture was diluted with methylene chloride and added with a saturatedaqueous solution of sodium chloride to form two layers. The organiclayer obtained by separation was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crudely purified product waspurified by chromatography on a silica gel column (hexane:ethylacetate=8:1), whereby the title compound (155 mg) was obtained as acolorless solid.

[3450]¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.44 (9H, s), 3.22 (2H, br s),3.49-3.62 (2H, br), 3.57-3.62 (2H, br), 7.56 (1H, dd, J=8.8, 2.0 Hz),7.79 (1H, d, J=8.8 Hz), 7.86 (1H, s), 7.87-7.92 (3H, m), 8.36 (1H, s).

Referential Example 2821-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazineHydrochloride

[3451] To a methylene chloride solution (0.5 ml) of4-(tert-butoxycarbonyl)-1-[(6-chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazine(140 mg) was added a saturated solution (0.5 ml) of hydrochloride inethanol. The resulting mixture was stirred at room temperature for 14hours. Ethanol was added to the reaction mixture. After the sufficientremoval of hydrochloric acid by azeotropy, the residue was dried using avacuum pump, whereby the title compound (119 mg) was obtained as acolorless solid.

[3452]¹H-NMR (DMSO-d₆) δ: 3.17 (4H, br s), 3.50-3.95 (4H, br), 7.44 (2H,t, J=3.9 Hz), 7.57 (2H, d, J=8.8 Hz), 7.66 (1H, t, J=3.9 Hz), 7.92 (2H,d, J=8.8 Hz), 8.36 (1H, d, J=7.8 Hz), 9.21 (2H, d, J=3.9 Hz).

[3453] MS (FAB) m/z: 339 [(M+H)⁺, Cl³⁵], 341 [(M+H)⁺, Cl³⁷].

Referential Example 2834-(tert-Butoxycarbonyl)-2,2-dimethyl-1-[4-(pyridin-4-yl)benzoyl]piperazine

[3454] To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperazine(173 mg) in a mixture of N,N-dimethylformamide (2.5 ml) andtriethylamine (1.0 ml) was added (4-nirophenyl) 4-(4-pyridyl)benzoate(330 mg). The resulting mixture was stirred at 60° C. for 5 days. Thereaction mixture was diluted with methylene chloride and then added witha saturated aqueous solution of sodium chloride to form two layers. Theorganic layer obtained by separation was washed with a saturated aqueoussolution of sodium bicarbonate and an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crudely purified product was purified bychromatography on a silica gel column (methylenechloride:methanol=50:1), whereby the title compound (199 mg) wasobtained as colorless amorphous.

[3455]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 1.61 (6H, s), 3.45-3.56 (6H, m),7.50 (2H, d, J=5.9 Hz), 7.51 (2H, d, J=7.8 Hz), 7.67 (2H, d, J=7.8 Hz),8.69 (1H, d, J=5.9 Hz)

[3456] MS (FAB) m/z: 369 (M+H)⁺.

Referential Example 2841,4-bis(tert-Butoxycarbonyl)-2-(2-hydroxyethyl)piperazine

[3457] In methanol (200 ml) and concentrated hydrochloric acid (5.4 ml)was dissolved 1,4-dibenzyl-2-(2-hydroxyetyl)piperazine (19.2 g).Palladium hydroxide (1.02 g) was then suspended in the resultingsolution. The resulting suspension was vigorously shaken at roomtemperature for 15.5 hours under a hydrogen gas atmosphere of 1atmospheric pressure. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue thus obtained was addedwith methylene chloride (250 ml), methanol (50 ml) anddiisopropylethylamine (20.0 ml) to dissolve the former in the latter.Under ice cooling, di-tert-butyl dicarbonate (27.0 g) was added and theresulting mixture was stirred at room temperature for 18.5 hours. Thesolvent was distilled off under reduced pressure. The residue wassubjected to chromatography on a silica gel column (hexane:ethylacetate=9:1→hexane:ethyl acetate=1:1). Hexane was added to the residueto solidify the same, whereby the title compound (16.1 g) was obtainedas colorless powder.

[3458]¹H-NMR (CDCl₃) δ: 1.46, 1.48 (18H, each s), 1.30-1.90 (2H, m),2.70-4.40 (10H, m).

[3459] MS (FAB) m/z: 331 (M+H)⁺.

Referential Example 2851,4-Bis(tert-butoxycarbonyl)-2-formylmethylpiperazine

[3460] In methylene chloride (150 ml) was dissolved1,4-bis(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine. Under icecooling, N-methylmorpholine (2.14 g) and tetra-n-propylammoniumperruthenate (0.97 g) were added to the reaction mixture, followed bystirring at room temperature for 17 hours. The reaction mixture was thendistilled off under reduced pressure. The residue was subjected tochromatography on a silica gel column (hexane:ethyl acetate=9:1 to 2:1),whereby the title compound (3.11 g) was obtained as colorless powder.

[3461]¹H-NMR (CDCl₃) δ: 1.45 (18H, s), 2.50-3.10 (15H, m), 3.70-4.20(3H, m), 4.66 (1H, br), 9.76 (1H, s).

[3462] MS (FAB) m/z: 329 (M+H)⁺.

Referential Example 2861,4-Bis(tert-butoxycarbonyl)-2-[3-(thien-2-yl)-2-propenyl]piperazine

[3463] In tetrahydrofuran (50 ml) was dissolved1,4-bis(tert-butoxycarbonyl)-2-formylmethylpiperazine (1.01 g). Underice cooling, a solution of [(thien-2-yl)methyl]phosphonium (1.62 g) inchloroform (100 ml) was added to the resulting solution, followed by thedropwise addition of 1,8-diazabicyclo[5.4.0]-7-undecene (620 μl). Theresulting mixture was stirred at room temperature for 15 hours. Thereaction mixture was distilled under reduced pressure. The residue wassubjected to chromatography on a silica gel column (hexane:ethylacetate=9:1 to 2:1), whereby the title compound (1.13 g) was obtained asa pale yellow oil.

[3464]¹H-NMR (CDCl₃) δ: 1.30-1.50 (18H, m), 2.30-2.50 (1H, m), 2.50-3.10(4H, m), 3.40-4.60 (4H, m), 5.45-6.05 (1H, m), 6.50-6.65 (1H, m),6.85-7.30 (3H, m).

[3465] MS (FAB) m/z: 409 (M+H)⁺.

Referential Example 2871,4-Bis(tert-butoxycarbonyl)-2-[3-(thien-2-yl)propyl]piperazine

[3466] In methanol (70 ml) was dissolved1,4-bis(tert-butoxycarbonyl)-2-[3-(thien-2-yl)-2-propenyl]piperazine(1.01 g). In the resulting solution was suspended 10% palladium-carbon(50% wet, 431 mg), followed by vigorous shaking at room temperature for6 hours under a hydrogen gas atmosphere of 1 atmospheric pressure. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure. The residue was subjected to chromatography on asilica gel column (hexane:ethyl acetate=9:1 to 2:1), whereby the titlecompound (975 mg) was obtained as colorless powder.

[3467]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.46 (9H, s), 1.50-1.80 (4H, m),2.70-3.00 (5H, m), 3.80-4.20 (4H, m), 7.75-7.80 (1H, m), 7.85-7.95 (1H,m), 7.10 (1H, d, J=5.1 Hz).

[3468] MS (FAB) m/z: 411 (M+H)⁺.

Referential Example 2881-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[3-(thien-2-yl)propyl]piperazine

[3469] In the same manner as in Referential Example 220, the titlecompound was obtained.

[3470]¹H-NMR (CDCl₃) δ: 1.35-1.80 (4H, m), 2.55-2.65 (1H, m), 2.75-3.10(6H, m), 3.77 (2H, t, J=10.9 Hz), 6.70-6.80 (1H, m), 6.85-6.95 (1H, m),7.05-7.15 (1H, m), 7.35-7.0 (4H, m), 7.50-7.60 (2H, m), 8.00-8.10 (2H,m), 8.22 (1H, d, J=9.3 Hz).

[3471] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁷].

Referential Example 2891,4-Bis(tert-butoxycarbonyl)-2-[3-(3,4-dimethoxyphenyl)-2-propenyl]piperazine

[3472] In the same manner as in Referential Example 286, the titlecompound was obtained.

[3473]¹H-NMR (CDCl₃) δ: 1.40-1.50 (18H, m), 2.35-3.10 (5H, m), 3.75-4.30(10H, m), 5.50-6.05 (1H, m), 6.30-6.50 (1H, m), 6.75-6.90 (3H, m).

[3474] MS (FAB) m/z: 463 (M+H)⁺.

Referential Example 2901,4-Bis(tert-butoxycarbonyl)-2-[3-(3,4-dimethoxyphenyl)propyl]piperazine

[3475] In the same manner as in Referential Example 287, the titlecompound was obtained.

[3476]¹H-NMR (CDCl₃) δ: 1.45 (18H, s), 1.20-1.70 (4H, m), 2.50-3.05 (5H,m), 3.70-4.20 (10H, m), 6.65-6.80 (3H, m).

[3477] MS (FAB) m/z: 465 (M+H)⁺.

Referential Example 2911-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[3-(3,4-dimethoxyphenyl)propyl]piperazine

[3478] In the same manner as in Referential Example 220, the titlecompound was obtained.

[3479]¹H-NMR (CDCl₃) δ: 1.30-1.70 (4H, m), 2.50-2.65 (3H, m), 2.75-3.05(4H, m), 3.70-3.90 (8H, m), 6.0-6.70 (2H, m), 6.75-6.80 (1H, m),7.35-7.50 (4H, m), 7.50-7.60 (2H, m), 8.02 (2H, d, J=8.1 Hz), 8.22 (1H,d, J=9.0 Hz).

[3480] MS (FAB) m/z: 619 [(M+H)⁺, Cl³⁵], 621 [(M+H)⁺, Cl³⁷].

Referential Example 2921,4-Bis(tert-butoxycarbonyl)-2-(2-bromoethyl)piperazine

[3481] In methylene chloride (70 ml) were dissolved1,4-bis(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (2.01 g) andtriphenylphosphine (1.98 g). Under ice cooling, carbon tetrabromide(3.07 g) was added to the resulting solution, followed by stirring atroom temperature for 2.5 hours. The reaction mixture was extracted witha 10% aqueous solution of sodium thiosulfate. The organic layer waswashed with saturated aqueous NaCl solution, dried over anhydrous sodiumsulfate an distilled under reduced pressure to remove the solvent. Theresidue was subjected to column chromatography (hexane:ethylacetate=4:1) using as a carrier silica gel, whereby the title compound(2.20 g) was obtained as colorless powder.

[3482]¹H-NMR (CDCl₃) δ: 1.47, 1.48 (18H, each s), 2.00-2.20 (2H, m),2.70-3.00 (3H, m), 3.30-3.45 (2H, m), 3.80-4.40 (4H, m).

Referential Example 2931,4-Bis(tert-butoxycarbonyl)-2-[2-[(pyrrolidin-1-yl)sulfonyl]ethyl]piperazine

[3483] Sodium sulfite (1.68 g) was dissolved in water (90 ml). Under icecooling, a solution of1,4-bis(tert-butoxycabonyl)-2-(2-bromoethyl)piperazine (2.20 g) inN,N-dimethylformamide (90 ml) was added to the reaction mixture,followed by stirring at 50° C. for 15 hours. The reaction mixture wasthen concentrated under reduced pressure. The residue was added withethanol and the insoluble matter was filtered off. The filtrate wasconcentrated under reduced pressure, whereby the crudely purifiedproduct (2.98 g) was obtained as a colorless paste. The crudely purifiedproduct was then dissolved in N,N-dimethylformamide (10 ml). Under icecooling, thionyl chloride (407 μl) was added dropwise, followed bystirring at 0° C. for 0.5 hour and at room temperature for 1 hour. Icewater (40 ml) was poured into the reaction mixture. After the removal ofthe insoluble matter, the residue was dried. The residue was thendissolved in methylene chloride. The resulting solution was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent, whereby pale yellow oil (524.9 mg) was obtained. Thecrudely purified product was then dissolved in methylene chloride (10ml), followed by the addition of diisopropylethylamine (500 μl) andpyrrolidine (220 μl) under ice cooling. The resulting mixture wasstirred at room temperature for 19 hours. The reaction mixture wasdistilled under reduced pressure. The residue was subjected to columnchromatography (hexane:ethyl acetate 1:1) using silica gel as a carrier,whereby the title compound (122 mg) was obtained as a pale yellow oil.

[3484]¹H-NMR (CDCl₃) δ: 1.47, 1.47 (18H, each s), 1.85-2.20 (6H, m),2.70-3.10 (5H, m), 3.30-3.40 (4H, m), 3.80-4.30 (4H, m).

Referential Example 2941-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[2-[(pyrrolidin-1-yl)sulfonyl]ethyl]piperazine

[3485] In the same manner as in Referential Example 220, the titlecompound was obtained.

[3486]¹H-NMR (CDCl₃) δ: 1.80-2.00 (6H, m), 2.60-2.70 (1H, m), 2.80-3.1(6H, m), 3.30-3.40 (4H, m), 3.65-3.85 (2H, m), 7.40-7.50 (4H, m),7.50-7.60 (2H, m), 8.01 (2H, d, J=7.8 Hz), 8.22 (2H, d, J=8.3 Hz).

[3487] MS (FAB) m/z: 601 [(M+H)⁺, Cl³⁵], 603 [(M+H)⁺, Cl^(37].)

Referential Example 295 4-(Chloro-2-methoxyphenyl)methanol

[3488] In tetrahydrofuran (100 ml) was dissolved4-chloro-2-methoxyphenylcarboxylic acid (20.1 g), followed by purgingwith argon. A borane-methylsulfide complex (11.0 ml) was added dropwiseto the reaction mixture. After completion of the dropwise addition, whenreflux due to the emission of heat generated by the reaction stopped,stirring was conducted at room temperature for 2 hours. Under icecooling, water was added to the reaction mixture. The resulting mixturewas extracted with ethyl acetate and a saturated aqueous solution ofsodium bicarbonate. The organic layer thus obtained was washed withsaturated aqueous NaCl solution, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent, whereby thetitle compound (17.6 g) was obtained as pale yellow powder.

[3489]¹H-NMR (CDCl₃) δ: 2.25 (1H, s), 3.85 (3H, s), 4.63 (2H, s), 6.86(1H, d, J=1.8 Hz), 6.92 (1H, dd, J=8.2, 1.8 Hz), 7.21 (1H, d, J=8.2 Hz).

Referential Example 296 4-Chloro-1-formyl-2-methoxybenzene

[3490] In methylene chloride (80 ml) was dissolved(4-chloro-2-methoxyphenyl)methanol (3.69 g). Under ice cooling,molecular sieve 4A (4.57 g), N-methylmorpholine (2.81 g) andtetra-n-propylammonium perruthenate (420 mg) were added to the resultingsolution, followed by stirring at room temperature for 2.5 hours. Thereaction mixture was distilled under reduced pressure. The residue wassubjected to chromatography on a silica gel column (hexane:ethylacetate=9:1), whereby the title compound (3.07 g) was obtained as paleyellow oil.

[3491]¹H-NMR (CDCl₃) δ: 3.94 (3H, s), 6.99 (1H, d, J=2.0 Hz), 7.00-7.05(1H, m), 7.77 (1H, d, J=8.3 Hz), 10.39 (1H, s).

Referential Example 297 4-Chloro-2-methoxystyrene

[3492] In tetrahydrofuran (50 ml) was suspendedmethyltriphenylphosphonium bromide (5.03 g), followed by purging withargon. Under ice cooling, n-butyl lithium (a 1.59 mole solution, hexane)(9.80 ml) was added dropwise over 30 minutes. After completion of thedropwise addition, stirring was conducted at room temperature for 30minutes. Under ice cooling, a solution of4-chloro1-formyl-2-methoxybenzene (2.02 g) in tetrahydrofuran (15 ml)was added dropwise to the reaction mixture. After completion of thedropwise addition, stirring was conducted at room temperature for 3.5hours. Then, water was added to the reaction mixture under ice cooling.The reaction mixture was extracted with ethyl acetate. The extract waswashed with saturated aqueous NaCl solution, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was subjected to chromatography on a silica gel column(hexane:ethyl acetate=9:1), whereby the title compound (1.51 g) wasobtained as a pale yellow oil.

[3493]¹H-NMR (CDCl₃) δ: 3.83 (3H, s), 5.26 (1H, dd, J=11.2, 1.5 Hz),5.70 (1H, dd, J=17.8, 1.2 Hz), 6.80-7.00 (3H, m), 7.37 (1H, d, J=8.3Hz).

[3494] MS (FAB) m/z: 169 [(M+H)⁺, Cl³⁵], 171 [(M+H)⁺, Cl³⁷].

Referential Example 298 (4-Chloro-2-methoxystyryl)sulfonyl Chloride

[3495] Sulfuryl chloride (1.66 ml) was charged in a container, followedby purging with argon. Under ice cooling, N,N-dimethylformamide (1.7 ml)was added, followed by stirring at room temperature for 40 minutes. Tothe reaction mixture was added 4-chloro-2-methoxystyrene (2.05 g) andthe resulting mixture was stirred at 90° C. for 3 hours. Ice was addedand the resulting mixture was extracted with methylene chloride. Theextract was washed with saturated aqueous NaCl solution, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was subjected to column chromatography(hexane:ethyl acetate=9:1) using as a carrier silica gel, whereby thetitle compound (885 mg) was obtained as a pale yellow oil.

[3496]¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 6.98 (1H, d, J=2.0 Hz), 7.03 (1H,dd, J=8.3, 2.0 Hz), 7.38 (1H, d, J=8.3 Hz), 7.50 (1H, d, J=15.1 Hz),7.78 (1H, d, J=15.1 Hz).

[3497] MS (FAB) m/z: 266 [(M+H)⁺, Cl³⁵+Cl³⁵].

Referential Example 2991-(tert-Butoxycarbonyl)-4-[(E)-4-chloro-2-methoxystyrylsulfonyl]piperazine

[3498] In the same manner as in Referential Example 129, the titlecompound was synthesized. ¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 3.10-3.20 (4H,m), 3.50-3.60 (4H, m), 3.91 (3H, s), 6.82 (1H, d, J=15.6 Hz), 6.94 (1H,d, J=2.0 Hz), 6.97 (1H, dd, J=8.3, 2.0 Hz), 7.33 (1H, d, J=8.3 Hz), 7.56(1H, d, J=15.6 Hz).

[3499] MS (FAB) m/z: 416 [(M+H)⁺, Cl³⁵], 418 [(M+H)⁺, Cl³⁷].

Referential Example 3001-(5-Bromopyrimidin-2-yl)-4-[((E)-4-chloro-1-methoxystyryl)sulfonyl]piperazine

[3500] In methylene chloride (10 ml) was dissolved1-(tert-butoxycarbonyl)-4-[((E)-4-chloro-1-methoxystyryl)sulfonyl]piperazine(690 mg). Under ice cooling, trifluoroacetic acid (1.0 ml) was addeddropwise to the resulting solution, followed by stirring at roomtemperature for 1 hour. Methylene chloride (10 ml) was added further tothe reaction mixture and they were stirred at 0° C. for 23 hours and atroom temperature for 2 hours. The solvent was distilled off underreduced pressure. The residue was extracted with methylene chloride anda saturated aqueous solution of sodium bicarbonate. The organic layerwas washed with saturated aqueous NaCl solution, dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The resulting residue, that is,(5-bromopyrimidin-2-yl)carboxylic acid (467 mg) was dissolved in amixture of N,N-dimethylformamide (15 ml) and methylene chloride (15 ml),followed by the successive addition of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (366 mg),1-hydroxybenzotriazole hydrate (266 mg) and diisopropylethylamine (1.01ml) under ice cooling. The resulting mixture was stirred at roomtemperature for 25 hours. The solvent was then distilled off underreduced pressure. The residue was extracted with methylene chloride anda saturated aqueous solution of sodium bicarbonate. The organic layerwas washed with saturated aqueous NaCl solution, dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue was subjected to column chromatography(hexane:ethyl acetate=1:1 to 1:2) using as a carrier silica gel, wherebythe title compound (629 mg) was obtained as colorless powder.

[3501]¹H-NMR (CDCl₃) δ: 3.22 (2H, t, J=4.5 Hz), 3.33 (2H, t, J=4.6 Hz),3.52 (2H, t, J=4.4 Hz), 3.90-3.95 (2H, m), 6.83 (1H, d, J=15.6 Hz), 6.95(1H, s), 6.99 (1H, d, J=8.3 Hz), 7.33 (1H, d, J=8.3 Hz), 7.56 (1H, d,J=15.6 Hz), 8.80-8.90 (2H, m).

[3502] MS (FAB) m/z: 501 [(M+H)⁺, Cl³⁵, Br⁷⁹], 505 [(M+H)⁺, Cl³⁵, Br⁸¹and Cl³⁷, Br⁷⁹], 507 [(M+H)⁺, Cl³⁷, Br^(81].)

Referential Example 3012,cis-6-Bis(methoxycarbonylmethyl)-1-(5-bromopyrimidin-2-yl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3503] In a mixture of methylene chloride (30 ml) andN,N-dimethylformamide (200 μl) was dissolved5-bromo-2-pyrimidinecarboxylic acid (736 mg), followed by purging withargon. Under an argon atmosphere and ice cooling, oxalyl chloride (0.40ml) was added dropwise to the reaction mixture. The resulting mixturewas stirred at room temperature for 0.5 hour. The reaction mixture thusobtained was designated as “Reaction Mixture A”.

[3504] In methylene chloride (50 ml) was dissolved2,cis-6-bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(529 mg). Diisopropylethylamine (2.00 ml) was added to the reactionmixture under ice cooling, followed by purging with argon. ReactionMixture A prepared in advance was then added dropwise under ice coolingand the resulting mixture was stirred at room temperature for 11 hours.The reaction mixture was extracted with a saturated aqueous solution ofsodium bicarbonate. The organic layer was washed successively withdilute hydrochloric acid and saturated aqueous NaCl solution, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was subjected to column chromatography (0.5%˜1%methanol—methylene chloride) using as a carrier silica gel. The solventwas then distilled off under reduced pressure. A small amount ofmethylene chloride was added to the residue for crystallization, wherebythe title compound (432 mg) was obtained as pale yellow powder.

[3505]¹H-NMR (CDCl₃) δ: 2.40-3.00 (6H, m), 3.57-3.70 (8H, m), 3.90-4.00(1H, m), 4.90-5.00 (1H, m), 7.70-7.75 (1H, m), 7.80-7.85 (1H, m),8.15-8.30 (3H, m), 8.52 (1H, s), 9.07 (2H, s).

Referential Example 3021-(5-Bromopyrimidin-2-yl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)piperazine

[3506] In the same manner as in Referential Example 12, the titlecompound was synthesized.

[3507]¹H-NMR (CDCl₃) δ: 2.40-3.25 (5H, m), 3.45-3.55 (1H, m), 3.67, 3.72(3H, each s), 3.70-5.30 (4H, m), 7.60 (1H, dd, J=8.6, 1.7 Hz), 7.70-7.75(1H, m), 7.90-7.95 (3H, m), 8.25-8.30 (1H, m), 8.80, 8.81 (2H, each s).

[3508] MS (FAB) m/z: 567 [(M+H)⁺, Cl³⁵, Br⁷⁹], 569 [(M+H)⁺, Cl³⁵, Br⁸¹and Cl³⁷, Br⁷⁹], 571 [(M+H)⁺, Cl³⁷, Br⁸¹].

Referential Example 3031-(tert-Butoxycarbonyl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3509] In N,N-dimethylformamide (15 ml) was dissolved1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(2-hydroxyethyl)piperazine(739 mg) and imidazole (226 mg) Under ice cooling,tert-butylchlorodiphenylsilane (0.70 ml) was added to the resultingsolution, followed by stirring at room temperature for 23 hours. Thereaction mixture was distilled off under reduced pressure. The residuewas extracted with methylene chloride and a saturated aqueous solutionof sodium bicarbonate. The organic layer thus obtained was washed withdilute hydrochloric acid and saturated aqueous NaCl solution, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by column chromatography(hexane:ethyl acetate=2:1˜:2) using as a carrier silica gel, whereby thetitle compound (804 mg) was obtained as a pale yellow oil.

[3510]¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.31 (9H, s), 1.90-2.00 (2H, m),2.20-2.30 (1H, m), 2.30-2.40 (1H, m), 2.95-3.05 (1H, m), 3.60-3.80 (4H,m), 3.85-4.00 (1H, m), 4.35-4.45 (1H, m), 7.35-7.45 (6H, m), 7.55-7.60(1H, m), 7.65-7.75 (5H, m), 7.85-7.95 (3H, m), 8.26 (1H, s).

[3511] MS (FAB) m/z: 693 [(M+H)⁺, Cl³⁵], 695 [(M+H)⁺, Cl³⁷].

Referential Example 3043-[2-(tert-Butyldiphenylsilyloxy)ethyl]-1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3512] In nitrobenzene (5.0 ml) was dissolved1-(tert-butoxycarbonyl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]-4-(6-chloronaphthalen-2-yl)piperazine(91.2 mg), followed by stirring at 170 to 185° C. for 10.5 hours. Thereaction mixture was subjected to chromatography on a silica gel column(methylene chloride˜5% methanol—methylene chloride), whereby the titlecompound (43 mg) was obtained as a pale yellow oil.

[3513]¹H-NMR (CDCl₃) δ: 1.04 (9H, s), 1.50-1.65 (2H, m), 2.05-2.15 (1H,m), 2.35-2.45 (1H, m), 2.85-3.00 (3H, m), 3.65-3.75 (4H, m), 7.35-7.45(6H, m), 7.55-7.60 (1H, m), 7.60-7.65 (4H, m), 7.70-7.80 (1H, m),7.85-7.95 (3H, m), 8.28 (1H, s).

[3514] MS (FAB) m/z: 593 [(M+H)⁺, Cl³⁵], 595 [(M+H)⁺, Cl³⁷].

Referential Example 3051-(5-Bromopyrimidin-2-yl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3515] In a similar manner to Referential Example 12, the title compoundwas synthesized.

[3516]¹H-NMR (CDCl₃) δ: 0.90, 1.08 (9H, each s), 2.00-2.20 (2H, m),2.30-2.60 (2H, m), 3.15-5.20 (7H, m), 7.35-7.60 (10H, m), 7.65-7.75 (2H,m), 7.85-7.95 (3H, m), 8.20-8.30 (1H, m), 8.62, 8.79 (2H, each s).

[3517] MS (FAB) m/z: 777 [(M+H)⁺, Cl³⁵, Br⁷⁹], 779 [(M+H)⁺, Cl³⁵, Br⁸¹and Cl³⁷, Br⁷⁹], 781 [(M+H)⁺, Cl³⁷, Br⁸¹].

Referential Example 3062,cis-6-Bis(methoxycarbonylmethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazineand2,trans-6-bis(methoxycarbonylmethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[3518] In the same manner to Referential Example 192, the title compoundwere synthesized.

[3519] Instrumental data of2,cis-6-Bis(methoxycarbonylmethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[3520]¹H-NMR (CDCl₃) δ: 2.15-2.45 (6H, m), 2.90 (1H, br), 3.25-3.35 (2H,m), 3.65-3.75 (2H, m), 3.70 (6H, s), 7.43 (1H, dd, J=8.5, 1.7 Hz), 7.75(1H, s), 7.82 (1H, d, J=8.8 Hz), 7.85-7.90 (1H, m).

[3521] MS (FAB) m/z: 461 [(M+H)⁺, Cl³⁵], 463 [(M+H)⁺, Cl³⁷].

[3522] Instrumental data of2,trans-6-Bis(methoxycarbonylmethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[3523]¹H-NMR (CDCl₃) δ: 2.50-2.65 (6H, m), 2.85-2.95 (2H, m), 3.20-3.25(2H, m), 3.50-3.55 (2H, m), 3.70 (6H, s), 7.43 (1H, dd, J=8.6, 1.7 Hz),7.74 (1H, s), 7.82 (1H, d, J=8.8 Hz), 7.86 (1H, br s).

[3524] MS (FAB) m/z: 461 [(M+H)⁺, Cl³⁵], 463 [(M+H)⁺, Cl³⁷].

Referential Example 3072,cis-6-Bis(methoxycarbonylmethyl)-1-(5-bromopyrimidin-2-yl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[3525] In the same manner as in Referential Example 301, the titlecompound was synthesized.

[3526]¹H-NMR (CDCl₃) δ: 2.65-2.80 (3H, m), 2.90-3.00 (2H, m), 3.00-3.10(1H, m), 3.65-3.75 (2H, m), 3.68 (3H, s), 3.73 (3H, s), 4.00 (1H, d,J=12.2 Hz), 4.22 (1H, d, J=9.8 Hz), 5.20-5.30 (1H, m), 7.40-7.50 (1H,m), 7.77 (1H, s), 7.80-7.90 (2H, m), 8.80 (2H, s).

Referential Example 308 1,4-Dibenzyl-2-hydroxymethylpiperazine

[3527] In tetrahydrofuran (42 ml) was suspended lithium aluminum hydride(1.04 g). After a suspension of 1,4-dibenzyl-2-ethoxycarbonylpiperazine(12.5 g) in tetrahydrofuran (300 ml) was added dropwise, stirring wasconducted at room temperature for 89.5 hours. The reaction mixture wasice cooled and added with a saturated aqueous solution of sodium sulfateand a 3N aqueous solution of sodium hydroxide. The insoluble matter wasfiltered off and the solvent was distilled off under reduced pressure.The residue was dissolved in tetrahydrofuran. The resulting solution wasdried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent.

[3528] Lithium aluminum hydride (1.5 g) was suspended in tetrahydrofuran(50 ml), followed by purging with argon. The reaction mixture was heatedto 50° C. To the reaction mixture, a solution of the residue, which hadbeen obtained above, in tetrahydrofuran (50 ml) was added dropwise,followed by heating under reflux for 4.5 hours. The reaction mixture wasthen heated under reflux for 4.5 hours after the addition of lithiumaluminum hydride (0.87 g). Lithium aluminum hydride (0.87 g) was addedagain and the resulting mixture was heated under reflux for 4.5 hours.The reaction mixture was ice cooled and then added with a saturatedaqueous solution of sodium sulfate and a 3N aqueous solution of sodiumhydroxide. The insoluble matter was filtered off and the solvent wasdistilled off under reduced pressure. The residue was dissolved inmethylene chloride. The resulting solution was dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue was subjected to chromatography on a silica gelcolumn (methylene chloride—5% methanol—methylene chloride), whereby thetitle compound (8.42 g) was obtained as a pale red oil.

[3529]¹H-NMR (CDCl₃) δ: 2.30-2.70 (5H, m), 2.90-3.00 (1H, m), 3.40-3.50(4H, m), 3.58 (1H, d, J=13.2 Hz), 3.90-4.10 (2H, m), 7.20-7.35 (10H, m).

[3530] MS (FAB) m/z: 297 (M+H)⁺.

Referential Example 3092-(tert-Butyldiphenylsilyloxy)methyl-1,4-dibenzylpiperazine

[3531] In N,N-dimethylformamide (20 ml) were dissolved1,4-dibenzyl-2-hydroxymethylpiperazine (1.11 g) and imidazole (347 mg).Under ice cooling, tert-butylchlorodiphenylsilane (1.17 ml, 1.24 g) wasadded to the reaction mixture, followed by stirring at room temperaturefor 14.5 hours. The solvent was distilled off under reduced pressure.The residue was extracted with ethyl acetate and a saturated aqueoussolution of sodium bicarbonate. The organic-layer was then washed withsaturated aqueous NaCl solution, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue wassubjected to column chromatography (hexane:ethyl acetate=9:1→8:2) usingas a carrier silica gel, whereby the title compound (1.42 g) wasobtained.

[3532]¹H-NMR (CDCl₃) δ: 0.98 (9H, s), 2.15-2.30 (3H, m), 2.50-2.55 (1H,m), 2.60-2.70 (2H, m), 2.80-2.90 (1H, m), 3.24 (1H, d, J=13.7 Hz),3.40-3.50 (2H, m), 3.60-3.70 (1H, m), 3.90-4.00 (2H, m), 7.15-7.45 (16H,m), 7.55-7.65 (4H, m).

[3533] MS (FAB) m/z: 535 (M+H)⁺.

Referential Example 3103-(tert-Butyldiphenylsilyloxy)methyl-1-(6-chloprobenzo[b]thien-2-yl)piperazine

[3534] In the same manner as in Referential Example 192, the titlecompound was obtained.

[3535]¹H-NMR (CDCl₃) δ: 1.02 (9H, s), 2.30-2.40 (1H, m), 2.45-2.65 (1H,m), 2.90-3.15 (3H, m), 3.50-3,70 (4H, m), 7.35-7.45 (7H, m), 7.55-7.65(4H, m), 7.71 (1H, s), 7.75-7.85 (2H, m).

[3536] MS (FAB) m/z: 585 [(M+H)⁺, Cl³⁵], 587 [(M+H)⁺, Cl³⁷].

Referential Example 3111-(5-Bromopyrimidin-2-yl)carbonyl-2-(tert-butyldiphenylsilyloxymethyl-4-(6-chloprobenzo[b]thien-2-yl)piperazine

[3537] In the same manner as in Referential Example 12, the titlecompound was obtained.

[3538]¹H-NMR (CDCl₃) δ: 1.02, 1.08 (9H, each s), 2.50-2.80 (2H, m),2.95-3.70 (2H, m), 3.80-4.25 (4H, m), 4.55-5.10 (1H, m), 7.35-7.50 (7H,m), 7.50-7.55 (1H, m), 7.60-7.65 (1H, m), 7.70-7.90 (5H, m), 8.65, 8.81(2H, s).

[3539] MS (FAB) m/z: 769 [(M+H)⁺, Cl³⁵, Br⁷⁹], 771 [(M+H)⁺, Cl³⁵, Br⁸¹and Cl³⁷, Br⁷⁹], 773 [(M+H)⁺, Cl³⁷, Br⁸¹].

Referential Example 312 1,4-Dibenzyl-2-(2-hydroxyethyl)piperazine

[3540] In the same manner as in Referential Example 308, the titlecompound was obtained.

[3541]¹H-NMR (CDCl₃) δ: 1.80-1.90 (1H, m), 2.00-2.10 (1H, m), 2.25-2.35(2H, m), 2.35-2.45 (1H, m), 2.45-2.55 (1H, m), 2.60-2.70 (1H, m),2.75-2.85 (1H, m), 2.85-2.95 (1H, m), 3.39 (1H, d, J=12.7 Hz), 3.49 (1H,d, J=1.5 Hz), 3.70-3.80 (1H, m), 3.80-3.90 (1H, m), 4.16 (1H, d, J=12.7Hz), 7.20-7.40 (10H, m).

Referential Example 3132-[2-(tert-Butyldiphenylsilyloxy)ethyl]-1,4-dibenzylpiperazine

[3542] In the same manner as in Referential Example 309, the titlecompound was obtained.

[3543]¹H-NMR (CDCl₃) δ: 0.99 (9H, s), 1.75-1.95 (2H, m), 2.10-2.20 (3H,m), 2.40-2.50 (1H, m), 2.50-2.65 (3H, m), 3.10-3.20 (1H, m), 3.30-3.50(2H, m), 3.60-3.75 (2H, m), 3.83 (1H, d, J=13.2 Hz), 7.15-7.25 (10H, m),7.25-7.40 (6H, m), 7.55-7.65 (4H, m).

[3544] MS (FAB) m/z: 549 (M+H)⁺.

Referential Example 3143-[2-(tert-Butyldiphenylsilyloxy)ethyl]-1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[3545] In the same manner as in Referential Example 192, the titlecompound was obtained.

[3546]¹H-NMR (CDCl₃) δ: 1.04 (9H, s), 1.50-2.00 (3H, m), 2.20-2.30 (1H,m), 2.50-2.60 (1H, m), 2.85-3.05 (3H, m), 3.65-3.80 (4H, m), 7.35-7.45(7H, m), 7.60-7.65 (4H, m), 7.72 (1H, s), 7.75-7.85 (2H, m).

[3547] MS (FAB) m/z: 599 [(M+H)⁺, Cl³⁵], 601 [(M+H)⁺, Cl³⁷].

Referential Example 3151-(5-Bromopyrimidin-2-yl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[3548] In the same manner as in Referential Example 12, the titlecompound was obtained.

[3549]¹H-NMR (CDCl₃) δ: 0.90, 1.07 (9H, each s), 2.00-2.15 (2H, m),2.50-2.80 (2H, m), 3.15-5.25 (7H, m), 7.35-7.90 (16H, m), 8.64, 8.81(2H, each s).

[3550] MS (FAB) m/z: 783 [(M+H)⁺, Cl³⁵, Br⁷⁹], 785 [(M+H)⁺, Cl³⁵, Br⁸¹and Cl³⁷, Br⁷⁹], 787 [(M+H)⁺, Cl³⁷, Br⁸¹].

Referential Example 3161-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-3-(methoxycarbonylmethyl)piperazine

[3551] In the same manner as in Referential Example 192, the titlecompound was obtained.

[3552]¹H-NMR (CDCl₃) δ: 2.30-2.50 (3H, m), 2.63 (1H, dt, J=3.4, 11.0Hz), 2.90-3.10 (2H, m), 3.20-3.30 (1H, m), 3.60-3.70 (2H, m), 3.69 (3H,s), 7.44 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, s), 7.82 (1H, d, J=8.3 Hz),7.85-7.90 (1H, m).

[3553] MS (FAB) m/z: 389 [(M+H)⁺, Cl³⁵], 391 [(M+H)⁺, Cl³⁷].

Referential Example 3171-[(5-Bromopyrimidin-2-yl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)piperazine

[3554] In the same manner as in Referential Example 12, the titlecompound was obtained.

[3555]¹H-NMR (CDCl₃) δ: 2.60-3.30 (5H, m), 3.50-5.40 (4H, m), 3.68, 3.73(3H, each s), 7.45 (1H, dd, J=8.5, 1.7 Hz), 7.76, 7.77 (1H, each s),7.80-7.85 (1H, m), 7.87 (1H, s), 8.83, 8.84 (2H, each s).

[3556] MS (FAB) m/z: 573 [(M+H)⁺, Cl³⁵], 575 [(M+H)⁺, Cl³⁷].

Referential Example 318(2RS)-2-(N-tert-Butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene

[3557] In dimethylformamide (25 ml),(2RS)-6-methoxycarbonyl-2-toluenesulfonyloxymethyl-1,2,3,4-tetrahydronaphthalene(2.56 g) was dissolved. Sodium azide (0.92 g) was added to the resultingsolution, followed by stirring at an external temperature of about 50°C. for 14 hours. The reaction mixture was concentrated under reducedpressure. The concentrate was diluted with ethyl acetate, washed withwater and then dried over sodium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was dissolved intetrahydrofuran (35 ml). Triphenylphosphine (1.82 g) was added to theresulting solution, followed by stirring at an external temperature ofabout 50° C. for 21 hours. After about 28% aqueous ammonia (15 ml) wasadded and the resulting mixture was stirred for 3 hours, the reactionmixture was concentrated under reduced pressure. The concentrate wasextracted with diethyl ether. Dilute hydrochloric acid was added to theextract to make it acidic and water layer was separated. To theresulting water layer, a dilute aqueous solution of sodium hydroxide wasadded to make it alkaline, followed by extraction with dichloromethane.The extract was dried over sodium sulfate and distilled under reducedpressure to remove the solvent. The resulting residue was dissolved indichloromethane (15 ml). To the resulting solution, a solution ofdi-tert-butyl dicarbonate (1.80 g) in dichloromethane (5 ml) was addedunder ice cooling, followed by stirring at room temperature for 2 hours.The residue obtained by distilling off the solvent under reducedpressure was purified by chromatography on a silica gel column (30 g ofsilica gel, dichloromethane˜dichloromethane:methanol=50:1) andrecrystallized from a mixed solvent of n-hexane and ethyl acetate,whereby colorless crystals (1.56 g, 71%) were obtained.

[3558]¹H-NMR (CDCl₃) δ: 1.40-1.60 (1H, m), 1.46 (9H, s), 1.90-2.10 (2H,m), 2.50 (1H, dd, J=17.1, 10.7 Hz), 2.70-3.00 (3H, m), 3.10-3.30 (2H,m), 3.89 (3H, s), 4.68 (1H, br), 7.12 (1H, d, J=7.8 Hz), 7.70-7.80 (2H,m).

[3559] Elementary analysis for C₁₈H₂₅NO₄

[3560] Calculated: C, 67.69; H, 7.89; N, 4.39.

[3561] Found: C, 67.78; H, 7.61; N, 4.12.

Referential Example 3191-[[(6RS)-6-(N-tert-Butoxycarbonylaminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3562] In tetrahydrofuran (5 ml),(2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene(0.14 g) was dissolved. To the resulting solution, 1N sodium hydroxide(0.50 ml) was added, followed by stirring at room temperature for 3 daysand at an external temperature of about 50° C. for 20 hours. 1N Sodiumhydroxide (0.40 ml) was added further, followed by stirring at anexternal temperature of about 50° C. for 2 days. After the reactionmixture was concentrated under reduced pressure, dichloromethane anddilute hydrochloric acid were added to separate the organic layer. Theorganic layer was dried over anhydrous sodium sulfate and then distilledunder reduced pressure to remove the solvent. The residue was dissolvedin N,N-dimethylformamide (5 ml). To the resulting solution1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (0.19 g),N-methylmorpholine (0.05 ml),1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (86.0 mg) and1-hydroxybenzotriazole (71.0 mg) were added, followed by stirring atroom temperature for 18 hours. After the reaction mixture wasconcentrated under reduced pressure, the concentrate was diluted withethyl acetate and washed with water. The mixture was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (dichloromethane˜dichloromethane:methanol=100:1), whereby thetitle compound was obtained as a colorless oil (0.23 g, 86%).

[3563]¹H-NMR (CDCl₃) δ: 1.30-1.60 (1H, m), 1.45 (9H, s), 1.80-2.00 (2H,m), 2.43 (1H, dd, J=16.6, 10.7 Hz), 2.70-2.90 (3H, m), 3.00-3.20 (6H,m), 3.50-3.90 (4H, br), 4.69 (1H, br), 6.90-7.10 (3H, m), 7.59 (1H, dd,J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.30(1H, s).

[3564] MS (FAB) m/z: 598 [(M+H)⁺, Cl³⁵], 600 [(M+H)⁺, Cl³⁷].

Referential Example 320(2RS)-2-(N-tert-Butoxycarbonylaminomethyl)-6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene

[3565] In dichloromethane (10 ml), the(2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene(0.47 g) was dissolved. Aluminum diisobutylhydride (a 0.95M hexanesolution, 3.60 ml) was added dropwise to the resulting solution at anexternal temperature of −78° C., followed by stirring for 90 minuteswithout changing the temperature. Methanol was added to the reactionmixture and the mixture was heated to room temperature. The insolublematter was filtered off from filtration through Celite. The filtrate wasconcentrated under reduced pressure. The concentrate was diluted withdichloromethane, washed with water and dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(hexane:ethyl acetate=3:1), whereby colorless crystals (0.31 g, 72%) wasobtained. A portion of the resulting crystals was recrystallized from amixed solvent of hexane and ethyl acetate, whereby colorless crystalswere obtained.

[3566]¹H-NMR (CDCl₃) δ: 1.40-1.60 (1H, m), 1.46 (9H, s), 1.60-1.70 (1H,m), 1.90-2.00 (2H, m), 2.45 (1H, dd, J=16.6, 10.7 Hz), 2.70-2.90 (3H,m), 3.10-3.30 (2H, m), 4.62 (2H, d, J=5.9 Hz), 4.67 (1H, br), 7.00-7.20(3H, m).

[3567] Elementary analysis for C₁₇H₂₅NO₃

[3568] Calculated: C, 70.07; H, 8.65; N, 4.81.

[3569] Found: C, 70.21; H, 8.49; N, 4.75.

Referential Example 3211-[[(6RS)-6-(N-tert-Butoxycarbonylaminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3570] In dichloromethane (5 ml), the(2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene(0.19 g) was dissolved. Pyridinium chlorochromate (0.17 g) was added tothe resulting solution, followed by stirring at room temperature for 2hours. The reaction mixture was purified as it was by chromatography ona silica gel column (hexane:ethyl acetate=4:1), whereby a colorlesssolid (0.16 g) was obtained. The resulting solid was dissolved indichloromethane (8 ml), followed by the addition of1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (0.24g), triethylamine (80.0 μl) and sodium triacetoxyboron hydride (0.17 g).The resulting mixture was stirred at room temperature for 16 hours underan argon gas atmosphere. An aqueous solution of sodium bicarbonate wasadded to the reaction mixture. The resulting mixture was diluted withdichloromethane to separate the organic layer. The organic layer wasdried over sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=3:1), whereby a colorless viscous liquid(0.33 g, 86%) was obtained.

[3571]¹H-NMR (CDCl₃) δ: 1.30-1.50 (1H, m), 1.44 (9H, s), 1.80-2.00 (2H,m), 2.40 (1H, m), 2.51 (4H, br), 2.60-2.90 (3H, m), 3.09 (6H, br), 3.39(2H, s), 4.67 (1H, br), 6.90-7.00 (3H, m), 7.56 (1H, d, J=8.8 Hz), 7.77(1H, d, J=8.8 Hz), 7.80-8.00 (3H, m), 8.28 (1H, s).

[3572] MS (FAB) m/z: 584 [(M+H)⁺, Cl³⁵], 586 [(M+H)⁺, Cl³⁷].

Referential Example 322(2RS)-2-(tert-Butyldimethylsilyloxymethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene

[3573] In N,N-dimethylformamide (5 ml),(2RS)-2-hydroxymethyl-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene(1.71 g) was dissolved. To the resulting solution, imidazole (0.81 g)and tert-butyldimethylsilyl chloride (1.81 g) were added under icecooling, followed by stirring at room temperature for 14 hours. Afterthe addition of methanol, the mixture was concentrated under reducedpressure. The concentrate was diluted with ethyl acetate, washed withwater and then dried over anhydrous sodium sulfate. The residue obtainedby distilling off the solvent under reduced pressure was purified bychromatography (hexane:ethyl acetate=50:1), whereby a pale yellow solid(2.20 g, 85%) was obtained.

[3574]¹H-NMR (CDCl₃) δ: 0.06 (6H, s), 0.91 (9H, s), 1.40-1.60 (1H, m),1.90-2.10 (2H, m), 2.53 (1H, dd, J=17.1, 10.3 Hz), 2.80-3.00 (3H, m),3.58 (2H, d, J=5.9 Hz), 3.89 (3H, s), 7.14 (1H, d, J=7.8 Hz), 7.70-7.80(2H, m).

[3575] MS (FAB) m/z: 335 (M+H)⁺.

Referential Example 323(2RS)-2-(tert-Butyldimethylsilyloxymethyl)-6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene

[3576] In the same manner as in Referential Example 320, the titlecompound was obtained using(2RS)-2-(tert-butyldimethylsilyloxymethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthaleneas a starting material.

[3577]¹H-NMR (CDCl₃) δ: 0.07 (6H, s), 0.91 (9H, s), 1.30-1.50 (1H, m),1.50-1.60 (1H, m), 1.90-2.10 (2H, m), 2.48 (1H, m), 2.70-2.90 (3H, m),3.58 (2H, m), 4.62 (2H, d, J=5.9 Hz), 7.09 (3H, m).

[3578] MS (FAB) m/z: 307 (M+H)⁺.

Referential Example 324(2RS)-6-(N-tert-Butoxycarbonylaminomethyl)-2-(tert-butyldimethylsilyloxymethyl)-1,2,3,4-tetrahydronaphthalene

[3579] In dichloromethane (10 ml),(2RS)-2-(tert-butyldimethylsilyloxymethyl)-6-hydroxymethyl-1,2,3,4-tetrahydronaphthalene(1.00 g) was dissolved. Triethylamine (0.5 ml) was added to theresulting solution, followed by ice cooling. A solution ofmethanesulfonyl chloride (0.39 g) in dichloromethane (1 ml) was added tothe reaction mixture and the mixture was stirred at room temperature for9 hours. After washing with water, the reaction mixture was dried overanhydrous sodium sulfate. The residue obtained by distilling off thesolvent under reduced pressure was treated In the same manner as inReferential Example 318, whereby the title compound (1.10 g, 83%) wasobtained.

[3580]¹H-NMR (CDCl₃) δ: 0.06 (6H, s), 0.91 (9H, s), 1.40-1.60 (1H, m),1.46 (9H, s), 1.90-2.00 (2H, m), 2.45 (1H, m), 2.70-2.90 (3H, m), 3.57(2H, m), 4.24 (2H, m), 4.76 (1H, br), 7.00-7.10 (3H, m).

[3581] MS (FAB) m/z: 406 (M+H)⁺.

Referential Example 325(2RS)-6-(N-tert-Butoxycarbonylaminomethyl)-2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene

[3582] In tetrahydrofuran (10 ml),(2RS)-6-(N-tert-butoxycarbonylaminomethyl)-2-(tert-butyldimethylsilyloxymethyl)-1,2,3,4-tetrahydronaphthalene(1.09 g) was dissolved. Tetrabutylammonium fluoride (a 1.0Mtetrahydrofuran solution, 4.0 ml) was added to the resulting solution,followed by stirring at room temperature for 2 hours. Afterconcentration under reduced pressure, the reaction mixture was dilutedwith dichloromethane, washed with water an dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(hexane:ethyl acetate=3:1 to 2:1), whereby a colorless solid (0.77 g,98%) was obtained. A portion of the solid was recrystallized from amixed solvent of hexane and ethyl acetate, whereby colorless crystalswere obtained.

[3583]¹H-NMR (CDCl₃) δ: 1.40-1.60 (2H, m), 1.46 (9H, s), 1.90-2.10 (2H,m), 2.48 (1H, dd, J=16.6, 10.7 Hz), 2.70-3.00 (3H, m), 3.6-3.7 (2H, m),4.24 (2H, d, J=5.4 Hz), 4.78 (1H, br), 7.00-7.10 (3H, m).

[3584] Elementary analysis for C₁₇H₂₅NO₃

[3585] Calculated: C, 70.07; H, 8.65; N, 4.81.

[3586] Found: C, 70.02; H, 8.61; N, 4.46.

Referential Example 3261-[[(2RS)-6-(N-tert-Butoxycarbonylaminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3587] In dichloromethane (5 ml),(2RS)-6-(N-tert-butoxycarbonylaminomethyl)-2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene(0.17 g) was dissolved, followed by the addition of N-methylmorpholineN-oxide (0.13 g) and molecular sieves 4A (activated powder, 0.18 g).Under ice cooling, tetrapropylammonium perruthenate (10 mg) was addedand the mixture was stirred at room temperature for 1 hour. Diethylether was added to the reaction mixture. From the resulting mixture,insoluble matter was removed by filtration through Celite. The filtratewas distilled under reduced pressure. The residue was purified bychromatography on a silica gel column (dichloromethane) to yield thealdehyde compound. In the same manner as in Referential Example 321, areaction was effected using the resulting aldehyde compound, whereby thetitle compound (0.14 g, 41%) was obtained.

[3588]¹H-NMR (CDCl₃) δ: 1.20-1.40 (1H, m), 1.44 (9H, s), 1.80-2.00 (2H,m), 2.20-2.40 (3H, m), 2.50-2.60 (4H, m), 2.60-2.80 (3H, m), 3.11 (4H,m), 4.20 (2H, d, J=5.4 Hz), 4.79 (1H, br), 6.94 (3H, m), 7.57 (1H, dd,J=8.8, 1.5 Hz), 7.79 (1H, dd, J=8.8, 1.5 Hz), 7.90-8.00 (3H, m), 8.31(1H, s).

[3589] MS (FAB) m/z: 584 [(M+H)⁺, Cl³⁵], 586 [(M+H)⁺, Cl³⁷].

Referential Example 3271-[[(2RS)-6-(N-tert-Butoxycarbonylaminomethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3590] In carbon tetrachloride (2 ml), acetonitrile (2 ml) and water (3ml),(2RS)-6-(N-tert-butoxycarbonylaminomethyl)-2-hydroxymethyl-1,2,3,4-tetrahydronaphthalen(0.21 g) was dissolved. To the resulting solution, sodium periodate(0.48 g) and ruthenium trichloride hydrate (4 mg) were added, followedby stirring for 90 minutes. The reaction mixture was diluted withdichloromethane. The organic layer thus separated was dried overanhydrous sodium sulfate. The residue obtained by distilling off thesolvent under reduced pressure was added with diethyl ether. After thefiltration of insoluble matter, the filtrate was distilled under reducedpressure. The carboxylic acid compound thus obtained was reacted in thesame manner as in Referential Example 319, whereby the title compound(0.11 g, 25%) was obtained.

[3591]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.70-2.00 (2H, m), 2.60-2.90 (4H,m), 2.95 (1H, m), 3.11 (4H, m), 3.64 (2H, m), 3.76 (2H, m), 4.22 (2H, d,J=5.4 Hz), 4.82 (1H, br), 6.90-7.10 (3H, m), 7.59 (1H, d, J=8.8 Hz),7.77 (1H, d, J=8.8 Hz), 7.90-8.00 (3H, m), 8.31 (1H, s).

[3592] MS (FD) m/z: 597 (M⁺, Cl³⁵), 599 (M⁺, Cl³⁷)

Referential Example 3282-(N-tert-Butoxycarbonylaminomethyl)-7-methoxycarbonylnaphthalene

[3593] In the same manner as in Referential Example 324, a reaction waseffected using 2-hydroxymethyl-7-methoxycarbonylnaphthalene (1.01 g) asa starting material, whereby the title compound was obtained.

[3594]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.98 (3H, s), 4.50 (2H, d, J=5.4Hz), 4.99 (1H, br), 7.53 (1H, d, J=8.3 Hz), 7.80-7.90 (3H, m), 8.04 (1H,dd, J=8.3, 1.0 Hz), 8.57 (1H, s).

[3595] Elementary analysis for C₁₉H₂₁NO₄

[3596] Calculated: C, 68.55; H, 6.71; N, 4.44.

[3597] Found: C, 68.54; H, 6.70; N, 4.46.

Referential Example 3291-[[7-(N-tert-Butoxycarbonylaminomethyl)naphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3598] In the same manner as in Referential Example 319, a reaction waseffected using2-(N-tert-butoxycarbonylaminomethyl)-7-methoxycarbonylnaphthalene as astarting material, whereby the title compound was obtained.

[3599]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 3.12 (4H, br), 3.50-4.00 (4H, br),4.45 (2H, d, J=5.9 Hz), 5.01 (1H, br), 7.34 (1H, d, J=7.8 Hz), 7.45 (1H,d, J=8.3 Hz), 7.50-7.60 (1H, m), 7.66 (1H, s), 7.70-7.80 (4H, m),7.90-8.00 (3H, m), 8.30 (1H, s).

[3600] MS (FAB) m/z: 594 [(M+H)⁺, Cl³⁵], 596 [(M+H)⁺, Cl³⁷].

Referential Example 3301-[[7-(N-tert-Butoxycarbonylaminomethyl)naphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3601] In the same manner as in Referential Example 320 or ReferentialExample 326, a reaction was effected using2-(N-tert-butoxycarbonylaminomethyl)-7-methoxycarbonylnaphthalene as astarting material, whereby the title compound was obtained.

[3602]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.50-2.70 (4H, m), 3.10 (4H, br),3.61 (2H, s), 4.44 (2H, d, J=5.4 Hz), 4.92 (1H, br), 7.30-7.40 (2H, m),7.50-7.70 (3H, m), 7.70-7.90 (3H, m), 7.90-8.00 (3H, m), 8.29 (1H, s).

[3603] MS (FAB) m/z: 580 [(M+H)⁺, Cl³⁵], 582 [(M+H)⁺, Cl³⁷].

Referential Example 3312-(N-tert-Butoxycarbonylaminomethyl)-6-methoxycarbonylnaphthalene

[3604] In a mixed solvent of tetrahydrofuran (40 ml) and methanol (8ml), dimethyl 2,6-naphthalenedicarboxylate (2.00 g) was suspended. Tothe resulting suspension, sodium borohydride (0.98 g) was added underice cooling, followed by stirring at room temperature for 21 hours. Thereaction mixture was added with water and then concentrated underreduced pressure. Ethyl acetate and dilute hydrochloric acid were addedto the residue to separate the organic layer. The organic layer wasdried over anhydrous sodium sulfate. The residue obtained by distillingoff the solvent under reduced pressure was purified by chromatography ona silica gel column (hexane:ethyl acetate=3:1), whereby colorlesscrystals (1.23 g, 70%) was obtained. The resulting crystals were reactedas in Referential Example 324, whereby the title compound was obtained.

[3605]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.98 (3H, s), 4.50 (2H, d, J=5.4Hz), 4.99 (1H, br), 7.47 (1H, d, J=8.3 Hz), 7.75 (1H, s), 7.84 (1H, d,J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.3 Hz), 8.58 (1H, s).

[3606] Elementary analysis for C₁₈H₂₁NO₄

[3607] Calculated: C, 68.55; H, 6.71; N, 4.44.

[3608] Found: C, 68.93; H, 6.70; N, 4.29.

Referential Example 332 Methyl 5-benzimidazolecarboxylate Hydrochloride

[3609] Under ice cooling, thionyl chloride (2.30 ml) was added dropwiseto methanol (50 ml). Then, 5-benzimidazolecarboxylic acid (5.00 g) wasadded, followed by heating under reflux for 5 hours. The reactionmixture was distilled under reduced pressure. The residue was pulverizedin diethyl ether, followed by collection through filtration, wherebycolorless crystals (6.36 g, 97%) was obtained.

[3610]¹H-NMR (DMSO-d₆) δ: 3.93 (3H, s), 7.96 (1H, d, J=8.8 Hz), 8.12(1H, d, J=8.8 Hz), 8.40 (1H, s), 9.66 (1H, s).

[3611] Elementary analysis for C₉H₈N₂O₂.HCl

[3612] Calculated: C, 50.84; H, 4.27; N, 13.17; Cl, 16.67.

[3613] Found: C, 50.64; H, 4.22; N, 13.12; Cl, 16.59.

Referential Example 333 MethylN-triphenylmethyl-5-benzimidazolecarboxylate

[3614] In dichloromethane (15 ml), methyl 5-benzimidazolecarboxylatehydrochloride (1.00 g) was suspended. To the resulting suspension,triethylamine (1.50 ml) and triphenylmethyl chloride (1.50 g) wereadded, followed by stirring at room temperature for 3 hours. Thereaction mixture was diluted with dichloromethane, washed with water,and dried over anhydrous sodium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was purified bychromatography on a silica gel column (hexane:ethyl acetate=2:1),whereby title compound (2.10 g, quant.) was obtained as a yellow solid.

[3615]¹H-NMR (CDCl₃) δ: 3.75 (2H, s), 3.89 (1H, s), 6.49 (⅓H, d, J=8.8Hz), 7.1-7.4 (16H, m), 7.61 (⅓H, dd, J=8.8, 1.5 Hz), 7.78 (⅔H, d, J=8.8Hz), 7.87 (⅔H, dd, J=8.8, 1.5 Hz), 7.96 (⅓H, s), 8.02 (⅔H, s).

[3616] MS (FAB) m/z: 419 (M+H)⁺.

Referential Example 334 Sodium thiazolo[5,4-c]pyridine-2-carboxylate

[3617] Ethyl thiazolo[5,4-c]pyridine-2-carboxylate (J. HeterocyclicChem., 27, 563(1990) (0.61 g) was dissolved in tetrahydrofuran (12 ml).To the resulting solution, a 1N aqueous sodium hydroxide solution (3 ml)was added, followed by stirring at room temperature for 30 minutes. Theinsoluble matter was collected by filtration. Without purification, itwas provided for the subsequent reaction as it was.

[3618]¹H-NMR (DMSO-d₆) δ: 7.95 (1H, d, J=5.9 Hz), 8.57 (1H, d, J=5.9Hz), 9.27 (1H, s).

Referential Example 3351-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3619] In the same manner as in Referential Example 321, the titlecompound was obtained using5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(WO94/21599) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride as starting materials.

[3620]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.53-2.62 (4H, m), 2.72 (2H, brs), 3.10 (4H, br s), 3.59 (2H, s), 3.66 (2H, br s), 4.38 (2H, s), 6.54(1H, s), 7.57 (1H, dd, J=8.8, 2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0 Hz),7.87-7.94 (3H, m), 8.29 (1H, s).

[3621] MS (FAB) m/z: 562 [(M+H)⁺, Cl³⁵], 564 [(M+H)⁺, Cl³⁷].

Referential Example 3363-(5-tert-Butoxycarbonyl-4,5,6,7-terahydrothieno[3,2-c]pyridin-2-yl)propionicAcid

[3622] Under ice cooling, sodium hydride (about 60% in oil, 126 mg) wasadded to tetrahydrofuran (10 ml). After stirring for 5 minutes, ethyldiethylphosphonoacetate (0.42 ml) was added dropwise and the resultingmixture was stirred for 30 minutes under ice cooling. To the reactionmixture, a solution of5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(WO94/21599) (360 mg) in tetrahydrofuran (10 ml) was added dropwise,followed by stirring for 1 hour under ice cooling. The reaction mixturewas then concentrated under reduced pressure. Ethyl acetate was added tothe concentrate. The mixture was washed with water and saturated aqueousNaCl solution and dried over anhydrous sodium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (hexane:ethylacetate=5:1), whereby a yellow oil (515 mg, quant) was obtained.

[3623] The resulting oil (1.38 g, 4.09 mmol) was dissolved in methanol(40 ml), followed by the addition of 10% palladium carbon (0.20 g). Themixture was subjected to catalytic reduction for 1 hour under normalpressure. After the removal of the catalyst by filtration, the filtratewas concentrated under reduced pressure, whereby pale yellow oil (1.41g, quant.) was obtained.

[3624] The oil (1.38 g, 4.07 mmol) was dissolved in tetrahydrofuran (15ml), followed by the addition of ethanol (10 ml) and a 1N aqueous sodiumhydroxide solution (8 ml). The resulting mixture was heated under refluxfor 30 minutes. To the reaction mixture, 1N hydrochloric acid and ethylacetate were added to separate the organic layer. The organic layer wasdried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent, whereby the title compound (1.28 g, quant.) wasobtained as a colorless oil.

[3625]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.70 (2H, t, J=7.3 Hz), 2.76 (2H,br s), 3.09 (2H, t, J=7.3 Hz), 3.70 (2H, s), 4.40 (2H, s), 6.51 (1H, s).

[3626] MS (FD) m/z: 311M⁺.

Referential Example 337(E)-3-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)acrylicAcid

[3627] In the same manner as in Referential Example 336 except thathydrolysis was carried out instead of catalytic hydrogenation, wherebythe title compound was obtained.

[3628]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.85 (2H, br s), 3.73 (2H, br s),4.47 (2H, s), 6.12 (1H, d, J=15.4 Hz), 6.98 (1H, s). 7.77 (1H, d, J=15.4Hz).

[3629] MS (FD) m/z: 309M⁺.

Referential Example 3381-(E)-3-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propenoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3630] In the same manner as in Referential Example 319, a reaction waseffected using(E)-3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)acrylicacid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochlorideas starting materials, whereby the title compound was obtained.

[3631]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.80 (2H, br s), 3.12 (4H, t,J=4.9 Hz), 3.46-3.86 (6H, m), 4.41 (2H, s), 6.39 (1H, d, J=15.1 Hz),6.83 (1H, s), 7.55-7.78 (3H, m), 7.89-7.92 (3H, m), 8.30 (1H, s).

[3632] MS (FD) m/z: 601 (M⁺, Cl³⁵), 603 (M⁺, Cl³⁷)

Referential Example 3391-[3-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propionyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3633] In tetrahydrofuran (10 ml),3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propionicacid (445 mg) was dissolved, followed by the successive dropwiseaddition of N-methylmorpholine (170 μl) and isobutyl chloroformate (210μl) at −20° C. After stirring at −20° C. for 10 minutes, a solution of1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (607 mg)which had been dissolved in dichloromethane (10 ml) was added. Afterstirring at −20° C. for 10 minutes, the reaction mixture was warmed upto room temperature. The reaction mixture was concentrated under reducedpressure. The residue was then dissolved in dichloroethane. Theresulting solution was washed with 1N hydrochloric acid, a saturatedaqueous solution of sodium bicarbonate and saturated aqueous NaClsolution, dried over anhydrous sodium sulfate and then distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=4:1 to 2:1),whereby the title compound (625 mg, 72%) was obtained.

[3634]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.53 (2H, t, J=7.5 Hz), 2.68 (2H,br s), 2.99-3.10 (6H, m), 3.51-3.55 (2H, m), 3.64 (2H, br s), 3.72-3.77(2H, m), 4.34 (2H, s), 6.43 (1H, s), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.74(1H, dd, J=8.8, 2.0 Hz), 7.88-7.94 (3H, m), 8.30 (1H, s).

[3635] MS (FAB) m/z: 604 [(M+H)⁺, Cl³⁵], 606 [(M+H)⁺, Cl³⁷].

Referential Example 3403-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propanal

[3636] In dichloromethane (100 ml), ethyl3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propionate(1.68 g) obtained in Referential Example 336 was dissolved. Afterstirring at −78° C. for 10 minutes, diisobutylaluminum hydride (a 0.98Mhexane solution, 7.50 ml) was slowly added dropwise. After stirring at−78° C. for 10 minutes, methanol (50 ml) was added, followed by warmingup to room temperature. The reaction mixture was concentrated underreduced pressure. To the residue, dichloromethane and a saturatedaqueous solution of ammonium chloride were added, followed by Celitefiltration. The organic layer was separated from the filtrate, washedwith saturated aqueous NaCl solution, dried over anhydrous sodiumsulfate and distilled to remove the solvent. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=5:1),whereby the title compound (935 mg, 55%) was obtained.

[3637]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.76 (2H, br s), 2.81 (2H, t,J=7.3 Hz), 3.09 (2H, t, J=7.3 Hz), 3.69 (2H, br s), 4.39 (2H, s), 6.49(1H, s), 9.81 (1H, s).

[3638] MS (FD) m/z: 295M⁺.

Referential Example 3411-[3-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3639] In the same manner as in Referential Example 321, a reaction waseffected using3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propanaland 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[3640]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.69-1.79 (2H, m), 2.36 (2H, t,J=7.3 Hz), 2.49-2.54 (4H, m), 2.65-2.75 (4H, m), 3.10 (4H, br s), 3.67(2H, br s), 4.37 (2H, s), 6.39 (1H, s), 7.57 (1H, dd, J=8.8, 2.0 Hz),7.78 (1H, dd, J=8.8, 2.0 Hz), 7.88-7.95 (3H, m), 8.30 (1H, s).

[3641] MS (FD) m/z: 589 (M⁺, Cl³⁵), 591 (M⁺, Cl³⁷).

Referential Example 3422-Aminomethyl-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[3642] In tetrahydrofuran (100 ml),5-tert-butoxycarbonyl-2-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(WO94/21599) (2.10 g) was dissolved. After the addition oftriphenylphosphine (2.66 g) and phthalimide (1.15 g), diethylazodicarboxylate (1.28 ml) was added dropwise, followed by stirring atroom temperature for 5 hours. The reaction mixture was concentratedunder reduced pressure. The residue was purified by chromatography on asilica gel column (hexane:ethyl acetate=4:1), whereby a colorless solidwas obtained. The resulting solid was dissolved in ethanol (40 ml),followed by the addition of hydrazine hydrate (0.39 ml). The resultingmixture was heated under reflux for 5 hours. The precipitate wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column(dichloromethane˜dichloromethane:methanol=25:1), whereby the titlecompound (448 mg, 21%) was obtained.

[3643]¹H-NMR (DMSO-d₆) δ: 1.42 (9H, s), 2.72 (2H, m), 3.60 (2H, m), 3.80(2H, s), 4.32 (2H, s), 6.64 (1H, s).

[3644] MS (FD) m/z: 268M⁺.

Referential Example 3431-[N-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3645] In tetrahydrofuran (100 ml),5-tert-butoxycarbonyl-2-aminomethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(150 mg) was dissolved. Under ice cooling, carbonyl diimidazole (136 mg)was added, followed by stirring at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in toluene (50 ml). Under ice cooling, triethylamine (0.23ml) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride(356 mg) were added, followed by stirring overnight at room temperature.The reaction mixture was diluted with ethyl acetate, washed with waterand saturated aqueous NaCl solution and then dried over anhydrous sodiumsulfate. The solvent was then distilled off under reduced pressure andthe residue was purified by chromatography on a silica gel column(hexane:ethyl acetate=3:1 to 1:1), whereby the title compound (303 mg,89%) was obtained.

[3646]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.70 (2H, br s), 3.07 (4H, t,J=4.9 Hz), 3.48 (4H, t, J=4.9 Hz), 3.66 (2H, br s), 4.36 (2H, br s),4.39 (2H, d, J=5.4 Hz), 4.69 (1H, t, J=5.4 Hz), 6.58 (1H, s), 7.58 (1H,dd, J=8.8, 2.0 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.87-7.93 (3H, m),8.30 (1H, s).

[3647] MS (FD) m/z: 604 (M⁺, Cl³⁵), 606 (M⁺, Cl³⁷)

Referential Example 3441-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3648] In the same manner as in Referential Example 319, the titlecompound was obtained using5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride.

[3649]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.79 (2H, br s), 3.12 (4H, t,J=4.9 Hz), 3.68 (2H, br s), 3.84 (4H, t, J=4.9 Hz), 4.42 (2H, br s),6.91 (1H, s), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0Hz), 7.90-7.97 (3H, m), 8.30 (1H, s).

[3650] MS (FD) m/z: 575 (M⁺, Cl³⁵), 577 (M⁺, Cl³⁷).

Referential Example 3451-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine

[3651] In the same manner as in Referential Example 319, the titlecompound was obtained using5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599) and1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-ethoxycarbonylpiperazine(WO96/10022) as starting materials.

[3652]¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.3 Hz), 1.47 (9H, s), 2.35-2.46(1H, m), 2.55-2.64 (1H, m), 2.80 (2H, br s), 3.15-3.20 (1H, m), 3.69(2H, br s), 3.75-3.85 (1H, m), 4.12 (2H, q, J=7.3 Hz), 4.20-4.36 (2H,m), 4.39-4.48 (3H, m), 6.96 (1H, s), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.75(1H, dd, J=8.8, 2.0 Hz), 7.88-7.94 (3H, m), 8.32 (1H, s).

[3653] MS (FAB) m/z: 648 [(M+H)⁺, Cl³⁵], 650 [(M+H)⁺, Cl³⁷].

Referential Example 3461-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine

[3654] In ethanol,1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (195 mg), triethylamine (0.2 ml) and sodium acetate (118mg) were suspended. Cyanogen bromide (114 mg) was added to the resultingsuspension, followed by stirring at room temperature for 2 hours. To theresidue obtained by concentration of the reaction mixture under reducedpressure, dichloromethane was added. The mixture was washed with waterand dried over anhydrous sodium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was purified bychromatography on a silica gel column (dichloromethane:methanol=100:1),whereby the title compound (51 mg, 28%) was obtained.

[3655]¹H-NMR (CDCl₃) δ: 2.93-2.98 (2H, m), 3.11-3.14 (4H, m), 3.49-3.55(2H, m), 3.81-3.84 (4H, m), 4.29 (2H, s), 6.89 (1H, s), 7.59 (1H, dd,J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.90-7.94 (3H, m), 8.30(1H, s).

[3656] MS (FAB) m/z: 501 [(M+H)⁺, Cl³⁵], 503 [(M+H)⁺, Cl³⁷].

Referential Example 3471-[N-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3657] In benzene (10 ml),5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599)(283 mg) was dissolved. To the resulting solution,triethylamine (0.14 ml) and diphenylphosphoryl azide (0.21 mg) wereadded, followed by heating under reflux for 2 hours. After the reactionmixture was cooled to room temperature,1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (347 mg)and triethylamine (0.28 ml) were added and the mixture was heated underreflux overnight. After cooling to room temperature, to the reactionmixture was added dichloromethane and a 3N aqueous sodium hydroxidesolution. The resulting mixture was separated and aqueous layer wasextracted with dichloromethane. The combined organic layer thusextracted was washed with 0.5N hydrochloric acid, a saturated aqueoussolution of sodium bicarbonate and saturated aqueous NaCl solution,dried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (hexane:ethyl acetate=3:1 to 2:1), whereby the titlecompound (284 mg, 48%) was obtained.

[3658]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.65 (2H, br s), 3.10 (4H, t,J=4.9 Hz), 3.57 (4H, t, J=4.9 Hz), 3.64 (2H, br s), 4.27 (2H, s), 6.15(1H, br s), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz),7.87-7.93 (3H, m), 8.28 (1H, s).

[3659] MS (FAB) m/z: 591 [(M+H)⁺, Cl³⁵], 593 [(M+H)⁺, Cl³⁷].

Referential Example 3481-[N-(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N-methylcarbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3660] In N,N-dimethylformamide (10 ml),1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(147 mg) was dissolved. To the resulting solution, sodium hydride (60%in oil, 22 mg) was added, followed by stirring at room temperature for30 minutes. After methyl iodide (0.023 ml) was added to the reactionmixture and the resulting mixture was stirred at room temperature for 90minutes, the residue obtained by the concentration of the reactionmixture under reduced pressure was added with ethyl acetate. Theresulting mixture was washed with water and saturated aqueous NaClsolution and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified bychromatography on a silica gel column (hexane:ethyl acetate=2:1),whereby the title compound (43 mg) was obtained.

[3661]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.63 (2H, br s), 3.01 (4H, t,J=4.9 Hz), 3.13 (3H, s), 3.40 (4H, t, J=4.9 Hz), 3.67 (2H, br s), 4.31(2H, s), 6.21 (1H, br s), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.72 (1H, dd,J=8.8, 2.0 Hz), 7.88-7.95 (3H, m), 8.27 (1H, s).

[3662] MS (FAB) m/z: 605 [(M+H)⁺, Cl³⁵], 607 [(M+H)⁺, Cl³⁷].

Referential Example 3491-[(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3663] In the same manner as in Referential Example 319, the titlecompound was obtained using6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylicacid (WO94/21599) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride as starting materials.

[3664]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.84 (2H, br s), 3.19 (4H, br),3.72 (2H, t, J=5.4 Hz), 3.87 (2H, br s), 4.54 (2H, s), 4.63 (2H, br s),7.57 (1H, dd, J=8.8, 2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.87-7.94(3H, m), 8.30 (1H, s).

[3665] MS (FAB) m/z: 577 [(M+H)⁺, Cl³⁵], 579 [(M+H)⁺, Cl³⁷].

Referential Example 3501-[(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine

[3666] In N,N-dimethylformamide (30 ml),6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylicacid (WO94/21599) (742 mg),1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-ethoxycarbonylpiperazinehydrochloride (WO96/10022) (1.00 g) andbenzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP®). (1.50 g) were dissolved. Triethylamine (0.40 ml) was added tothe resulting solution, followed by stirring overnight at roomtemperature. After the reaction mixture was concentrated under reducedpressure, ethyl acetate was added to the residue. The resulting mixturewas washed with water and saturated aqueous NaCl solution and then,dried over anhydrous sodium sulfate. The residue obtained by distillingoff the solvent under reduced pressure was purified by chromatography ona silica gel column (hexane:ethyl acetate=4:1), whereby the titlecompound (505 mg, 30%) was obtained.

[3667]¹H-NMR (CDCl₃) δ: 1.24-1.37 (3H, m), 1.47 (9H, s), 2.45-2.60 (1H,m), 2.62-2.71 (1H, m), 2.75-2.90 (2H, m), 3.65-3.94 (3H, m), 4.19-4.31(2H, m), 4.45-4.72 (4H, m), 5.35 (½H, br s), 5.71-5.77 (½H, m), 6.72(1H, br s), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.77 (1H, dd, J=8.8, 2.0 Hz),7.88-7.92 (3H, m), 8.33 (1H, s).

[3668] MS (FAB) m/z: 649 [(M+H)⁺, Cl³⁵], 651 [(M+H)⁺, Cl³⁷].

Referential Example 3511-[(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3669] In tetrahydrofuran (5 ml),1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine(487 mg) was dissolved. Methanol (5 ml) and a 1N aqueous sodiumhydroxide solution (3 ml) were added to the resulting solution, followedby stirring at room temperature for 4 hours. After the reaction mixturewas adjusted to pH 1 to 2 by the addition of 1N hydrochloric acid, ethylacetate was added to separate the organic layer. After drying overanhydrous sodium sulfate, the residue obtained by distilling off thesolvent under reduced pressure was dissolved in tetrahydrofuran (5 ml).To the resulting solution, N-methylmorpholine (0.09 ml) and isobutylchloroformate (0.11 ml) were added dropwise at −20° C. After stirring at−20° C. for 10 minutes, an ammonia-dichloromethane solution (0.50 ml)was added to the reaction mixture. The resulting mixture was stirred at−20° C. for 10 minutes, followed by the addition of 1N aqueoushydrochloric acid solution in ethanol (10 ml). The reaction mixture waswarmed up to room temperature. After the reaction mixture wasconcentrated under reduced pressure, the residue was dissolved indichloroethane. The resulting solution was washed with 1N hydrochloricacid. The organic layer was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column(dichloromethane˜dichloromethane:methanol=100:1), whereby the titlecompound (317 mg, 68%) was obtained.

[3670]¹H-NMR (DMSO-d₆) δ: 1.41 (9H, s), 2.39-2.86 (4H, m), 3.60-3.80(4H, m), 4.25-4.34 (1H, m), 4.36-4.34 (½H, m), 4.62 (2H, br s), 4.97(½H, br s), 5.44-5.52 (½H, m), 6.19 (½H, br s), 7.30-7.39 (1H, m),7.63-7.85 (3H, m), 8.15 (1H, d, J=8.8 Hz), 8.20-8.29 (2H, m), 8.48 (1H,s).

[3671] MS (FAB) m/z: 620 [(M+H)⁺, Cl³⁵], 622 [(M+H)⁺, Cl³⁷].

Referential Example 3521-[(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl-]-4-[(E)-4-chlorostyrylsulfonyl]piperazine

[3672] In the same manner as in Referential Example 319, the titlecompound was obtained using6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylicacid (WO94/21599) and 1-[(E)-4-chlorostyrylsulfonyl]piperazinehydrochloride as starting materials.

[3673]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.87 (2H, br s), 3.31 (4H, m),3.75 (2H, br s), 3.90 (2H, br s), 4.57 (2H, br s), 4.68 (2H, s), 6.64(1H, d, J=15.6 Hz), 7.28-7.35 (5H, m).

[3674] MS (FAB) m/z: 553 [(M+H)⁺, Cl³⁵], 555 [(M+H)⁺, Cl³⁷].

Referential Example 353(3S)-1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]-3-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidine

[3675] In the same manner as in Referential Example 321, a reaction waseffected using5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(WO94/21599) and (3S)-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidinetrifluoroacetate as starting materials, whereby the title compound wasobtained.

[3676]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 1.52-1.63 (1H, m), 2.03-2.12 (1H,m), 2.19-2.27 (1H, m), 2.35-2.54 (2H, m), 2.73-2.85 (3H, m), 3.59 (1H,d, J=13.9 Hz), 3.66 (1H, d, J=13.9 Hz), 3.70 (2H, br s), 3.88-3.95 (1H,m), 4.39 (2H, s), 4.99 (½H, s), 5.02 (½H, s), 6.49 (1H, s), 7.55 (1H,dd, J=8.8, 2.0 Hz), 7.82-7.90 (4H, m), 8.40 (1H, s).

[3677] MS (FD) m/z: 561 (M⁺, Cl³⁵), 563 (M⁺, Cl³⁷).

Referential Example 354(3S)-1-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-3-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidine

[3678] In the same manner as in Referential Example 319, the titlecompound was obtained using5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599) and(3S)-3-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidinetrifluoroacetate as starting materials.

[3679]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 1.80-2.08 (2H, m), 2.75 (2H, brs), 3.48-3.87 (6H, m), 3.88-4.05 (1H, m), 4.37 (2H, br s), 6.09 (1H, brs), 7.05-7.15 (1H, m), 7.55 (1H, dd, J=8.8, 1.5 Hz), 7.79-7.91 (4H, m),8.41 (1H, s).

[3680] MS (FAB) m/z: 576 [(M+H)⁺, Cl³⁵], 578 [(M+H)⁺, Cl³⁷].

Referential Example 355(3S)-3-[[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]amino]-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine

[3681] In the same manner as in Referential Example 321, a reaction waseffected using5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(WO94/21599) and(3S)-3-amino-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine asstarting materials, whereby the title compound was obtained.

[3682]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.60-1.69 (1H, m), 1.95-2.05 (1H,m), 2.72 (2H, br s), 3.11 (1H, dd, J=10.3, 4.4 Hz), 3.30-3.46 (4H, m),3.68 (2H, br s), 3.72 (2H, s), 4.36 (2H, s), 6.44 (1H, s), 7.56 (1H, dd,J=8.8, 2.0 Hz), 7.86-7.91 (4H, m), 8.36 (1H, s).

[3683] MS (FD) m/z: 561 (M⁺, Cl³⁵), 563 (M⁺, Cl³⁷)

Referential Example 356(3S)-3-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonylamino]-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine

[3684] In the same manner as in Referential Example 319, the titlecompound was obtained using5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599) and(3S)-3-amino-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine asstarting materials.

[3685]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.90-2.00 (1H, m), 2.11-2.22 (1H,m), 2.80 (2H, br s), 3.32-3.42 (1H, m), 3.44-3.57 (3H, m), 3.71 (2H, brs), 4.38 (2H, d, J=1.5 Hz), 4.40-4.49 (1H, m), 5.80-5.87 (1H, m), 6.96(1H, s), 7.54 (1H, dd, J=8.8, 1.5 Hz), 7.83-7.89 (3H, m), 7.90 (1H, d,J=8.8 Hz), 8.37 (1H, s).

[3686] MS (FAB) m/z: 576 [(M+H)⁺, Cl³⁵], 578 [(M+H)⁺, Cl³⁷].

Referential Example 3571-[(5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine

[3687] In the same manner as in Referential Example 319, the titlecompound was obtained using5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (WO94/21599) and1-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine hydrochloride asstarting materials.

[3688]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.01 (2H, br s), 2.78 (2H, br s),3.37-3.54 (4H, m), 3.68 (2H, br s), 3.78 (2H, t, J=6.1 Hz), 3.86 (2H, t,J=6.1 Hz), 4.39 (2H, s), 6.88 (1H, br s), 7.55 (1H, dd, J=8.8, 2.0 Hz),7.75-7.80 (1H, m), 7.83-7.90 (3H, m), 8.33 (1H, s).

[3689] MS (FD) m/z: 589 (M⁺, Cl³⁵), 591 (M⁺, Cl³⁷)

Referential Example 3581-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-cyanobenzofuran-2-yl)carbonyl]piperazine

[3690] In the same manner as in Referential Example 319, a reaction waseffected using 6-cyanobenzofuran-2-carboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[3691]¹H-NMR (CDCl₃) δ: 3.21 (4H, s), 3.95 (4H, s), 7.32 (1H, d, J=1.0Hz), 7.55 (1H, dd, J=8.3, 1.0 Hz), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.72(1H, d, J=8.3 Hz), 7.77 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, s), 7.88-7.95(3H, m), 8.32 (1H, s).

[3692] MS (FAB) m/z: 480 [(M+H)⁺, Cl³⁵], 482 [(M+H)⁺, Cl³⁷].

Referential Example 3591-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-cyanobenzothiophen-2-yl)carbonyl]piperazine

[3693] In the same manner as in Referential Example 319, a reaction waseffected using 5-cyanobenzothiophene-2-carboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[3694]¹H-NMR (CDCl₃) δ: 3.18 (4H, s), 3.89 (4H, s), 7.43 (1H, d, J=2.0Hz), 7.60 (1H, d, J=8.8 Hz), 7.73-7.80 (2H, m), 7.85-7.95 (4H, m), 8.10(1H, s), 8.32 (1H, s).

[3695] MS (FAB) m/z: 496 [(M+H)⁺, Cl³⁵], 498 [(M+H)⁺, Cl³⁷].

Referential Example 360 6-Methoxy-3,4-dihydroisoquinoline

[3696] In tetrahydrofuran (100 ml), 3-methoxyphenethylamine (75.0 g) wasdissolved. To the resulting solution, formic acid (60 ml) and aceticanhydride (108 ml) were added under ice cooling, followed by stirringovernight at room temperature. A saturated aqueous solution of sodiumbicarbonate was added to the reaction mixture to separate the organiclayer. The organic layer was washed with saturated aqueous NaCl solutionand then dried over anhydrous sodium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was dissolved inbenzene (200 ml), followed by the dropwise addition of phosphorusoxychloride (140 ml) under ice cooling. After stirring at 70° C. for 15minutes, the reaction mixture was successively added with ice and 2Nhydrochloric acid. The resulting mixture was stirred for 1 hour underice cooling. The water layer was separated from the reaction mixture,neutralized with potassium carbonate and then extracted withdichloromethane. The extract was dried over anhydrous sodium sulfate.The residue obtained by distilling off the solvent under reducedpressure was purified by chromatography on a silica gel column(dichloromethane˜dichloromethane:methanol=100:1), whereby the titlecompound (13.5 g, 17%) was obtained.

[3697]¹H-NMR (CDCl₃) δ: 2.72 (2H, t, J=7.3 Hz), 3.72 (2H, t, J=7.3 Hz),3.83 (3H, s), 6.68 (1H, d, J=2.4 Hz), 6.79 (1H, dd, J=8.3, 2.4 Hz), 7.22(1H, d, J=8.3 Hz), 8.25 (1H, s).

[3698] MS (FAB) m/z: 162 (M+H)⁺.

Referential Example 361 6-Methoxy-1,2,3,4-tetrahydroisoquinoline

[3699] In methanol (100 ml), 6-methoxy-3,4-dihydroisoquinoline (10.4 g)was dissolved. To the resulting solution, water (10 ml) and then sodiumborohydride (6.10 g) were added. The resulting mixture was stirred atroom temperature for 15 minutes. The reaction mixture was concentratedunder reduced pressure. The residue was dissolved in dichloromethane,followed by washing with water. The organic layer thus separated wasdried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (dichloromethane˜dichloromethane:methanol=100:15),whereby the title compound (7.95 g, 76%) was obtained.

[3700]¹H-NMR (CDCl₃) δ: 2.79 (2H, t, J=5.9 Hz), 3.12 (2H, t, J=5.9 Hz),3.76 (3H, s), 3.96 (2H, s), 6.62 (1H, s), 6.70 (1H, dd, J=8.3, 2.4 Hz),6.92 (1H, d, J=8.3 Hz)

[3701] MS (FAB) m/z: 164 (M+H)⁺.

Referential Example 362 6-Hydroxy-1,2,3,4-tetrahydroisoquinolineHydrochloride

[3702] In dimethyl sulfide (20 ml),6-methoxy-1,2,3,4-tetrahydroisoquinoline (7.75 g) was dissolved. Underice cooling, aluminum chloride (19.0 g) was added to the resultingsolution, followed by stirring at room temperature for 3 hours.Dichloromethane and dilute hydrochloric acid were added to separate thewater layer. The water layer was made basic by the addition of asaturated aqueous solution of sodium bicarbonate, followed by extractionwith dichloromethane. The extract was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was dissolved in saturated solution of hydrochloride in ethanol(100 ml). To the residue obtained by distilling off the solvent underreduced pressure, ethyl acetate was added. The solid thus precipitatedwas collected by filtration, whereby the title compound (7.91 g, 90%)was obtained.

[3703]¹H-NMR (DMSO-d₆) δ: 3.06 (2H, t, J=5.9 Hz), 3.43 (2H, m), 4.25(2H, s), 6.76 (1H, d, J=2.0 Hz), 6.83 (1H, dd, J=8.3, 2.0 Hz), 7.15 (1H,d, J=8.3 Hz), 9.71 (3H, br s).

[3704] MS (FAB) m/z: 150 (M+H)⁺.

Referential Example 3632-tert-Butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline

[3705] In methanol (100 ml), 6-hydroxy-1,2,3,4-tetrahydroisoquinolinehydrochloride (7.87 g) was dissolved. To the resulting solution,triethylamine (4.67 ml) and di-tert-butyl dicarbonate (13.95 g) wereadded, followed by stirring at room temperature for 3 hours. Ethylacetate was added to the residue obtained by concentration of thereaction mixture under reduced pressure. The resulting mixture waswashed with 1N hydrochloric acid, dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. The residuewas purified by chromatography on a silica gel column (hexane:ethylacetate=10:1 to 3:1), whereby the title compound (9.96 g, 94%) wasobtained.

[3706]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.75 (2H, t, J=5.9 Hz), 3.61 (2H,t, J=5.9 Hz), 4.48 (2H, s), 6.25 (1H, br s), 6.64 (1H, d, J=2.4 Hz),6.70 (1H, br s), 6.93 (1H, d, J=7.8 Hz).

Referential Example 3642-tert-Butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline

[3707] In pyridine (100 ml),2-tert-butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline (9.96 g)was dissolved. To the resulting solution, trifluorosulfonic anhydride(8.10 ml) was added dropwise under ice cooling, followed by stirring atroom temperature for 10 minutes. The reaction mixture was concentratedunder reduced pressure and the residue was purified by chromatography ona silica gel column (hexane:ethyl acetate=10:1 to 6:1), whereby thetitle compound (13.47 g, 88%) was obtained as a colorless solid.

[3708]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.87 (2H, t, J=5.9 Hz), 3.66 (2H,t, J=5.9 Hz), 4.59 (2H, s), 7.06 (1H, br s), 7.08 (1H, d, J=8.3 Hz),7.17 (1H, d, J=8.3 Hz).

[3709] Elementary analysis for C₁₅H₁₈F₃NO₅S

[3710] Calculated: C, 47.24; H, 4.76; F, 14.94; N, 3.67; S, 8.41.

[3711] Found: C, 47.34; H, 4.72; F, 15.25; N, 3.42; S, 8.65.

Referential Example 3652-tert-Butoxycarbonyl-6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline

[3712] In methanol (50 ml),2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline(1.34 g) was dissolved, followed by the addition of triethylamine (0.73ml), palladium (II) acetate (40 mg) and 1,3-(diphenylphosphino)propane(145 mg). Under a carbon monoxide gas stream, the resulting mixture wasstirred overnight at 70° C. The reaction mixture was concentrated underreduce pressure and the residue was purified by chromatography on asilica gel column (hexane:ethyl acetate=15:1), whereby the titlecompound (665 mg, 65%) was obtained.

[3713]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.88 (2H, m), 3.66 (2H, br s),3.91 (3H, s), 4.62 (2H, s), 7.17 (1H, d, J=7.8 Hz), 7.83 (1H, s), 7.84(1H, d, J=7.8 Hz).

Referential Example 3661-[(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3714] In the same manner as in Referential Example 319, the titlecompound was obtained using2-tert-butoxycarbonyl-6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinolineand 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[3715]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.76 (2H, t, J=5.4 Hz), 3.09 (4H,br), 3.60 (2H, t, J=5.4 Hz), 3.77 (4H, br), 4.52 (2H, s), 7.12-7.25 (3H,m), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz),7.88-7.95 (3H, m), 8.30 (1H, s).

[3716] MS (FAB) m/z: 570 [(M+H)⁺, Cl³⁵], 572 [(M+H)⁺, Cl³⁷].

Referential Example 3671-tert-Butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine

[3717] In methanol (1000 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[ethoxycarbonyl]piperazinehydrochloride (WO96/10022) (43.0 g) was dissolved, followed by theaddition of triethylamine (17.1 ml) and di-tert-butyl dicarbonate (27.0g). The resulting mixture was stirred at room temperature for 3 hours.The residue obtained by concentration of the reaction mixture underreduced pressure was added with ethyl acetate and the resulting mixturewas washed with 1N hydrochloric acid. The organic layer thus extractedwas dried over anhydrous sodium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was purified bychromatography on a silica gel column (hexane:ethyl acetate=8:1),whereby the title compound (46.0 g, 93%) was obtained as a colorlesssolid.

[3718]¹H-NMR (CDCl₃) δ: 1.24-1.32 (3H, m), 1.33-1.50 (9H, m), 2.37 (1H,m), 2.54 (1H, d, J=10.7 Hz), 3.15-3.41 (1H, m), 3.68-4.08 (2H, m),4.10-4.39 (3H, m), 4.62 (½H, br s), 4.82 (½H, br s), 7.58 (1H, dd,J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.87-7.94 (3H, m), 8.31(1H, d, J=2.0 Hz).

[3719] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

[3720] Elementary analysis for C₂₂H₂₇ClNO₆S

[3721] Calculated: C, 54.71; H, 5.63; Cl, 7.34; N, 5.80; S, 6.64.

[3722] Found: C, 54.89; H, 5.42; Cl, 7.15; N, 5.76; S, 6.24.

Referential Example 3681-tert-Butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine-2-carboxylicAcid

[3723] In tetrahydrofuran (40 ml),1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazine(23.0 g) was dissolved, followed by the addition of ethanol (40 ml) anda 3N aqueous sodium hydroxide solution (30 ml). The resulting mixturewas stirred at room temperature for 3 hours. To the reaction mixture, 1Nhydrochloric acid was added to make it acidic and then ethyl acetate wasadded to separate the organic layer. The organic layer was dried overanhydrous sodium sulfate. The solid precipitated by distilling off-thesolvent under reduced pressure was collected by filtration, whereby thetitle compound (23.8 g, quant.) was obtained as a colorless solid.

[3724]¹H-NMR (CDCl₃) δ: 2.41 (1H, m), 2.59 (1H, m), 3.15-3.38 (1H, m),3.70-4.08 (2H, m), 4.20-4.39 (1H, m), 4.72 (½H, br s), 4.91 (½H, br s),7.58 (1H, dd, J=8.8, J=2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.87-7.95(3H, m), 8.34 (1H, s).

[3725] Mass (FAB) m/Z: 455[(M+H)⁺, Cl³⁵], 457[(M+H)⁺, Cl³⁷].

[3726] Elementary analysis for C₂₀H₂₃ClNO₆S

[3727] Calculated: C, 52.80; H, 5.10; Cl, 7.79; N, 6.16; S, 7.05.

[3728] Found: C, 52.62; H, 5.00; Cl, 7.75; N, 6.22; S, 6.83.

Referential Example 3691-tert-Butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[3729] In the same manner as in Referential Example 367 or 368, thetitle compound was obtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[methoxycarbonylmethyl]piperazineas a starting material.

[3730]¹H-NMR (DMSO-d₆) δ: 1.38 (9H, s), 2.32 (1H, dt, J=12.2, 3.4 Hz),2.48 (1H, dd, J=12.2, 3.4 Hz), 2.61 (1H, dd, J=15.6, 5.9 Hz), 2.86 (1H,dd, J=15.6, 8.3 Hz), 3.13 (1H, s), 3.68 (3H, s), 3.74-4.08 (3H, m), 7.58(1H, dd, J=8.8, 2.0 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.89-7.94 (3H,m), 8.29 (1H, s).

[3731] MS (FAB) m/z: 469 [(M+H)⁺, Cl³⁵], 471 [(M+H)⁺, Cl³⁷].

[3732] Elementary analysis for C₂₂H₂₇ClN₂O₇S

[3733] Calculated: C, 54.71; H, 5.63; Cl, 7.34; N, 5.80; S, 6.64.

[3734] Found: C, 54.74; H, 5.69; Cl, 7.34; N, 5.84; S, 6.62.

Referential Example 3706-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[3735] In anhydrous tetrahydrofuran (500 ml),6-ethoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (WO94/21599)(21.0 g) was dissolved, followed by the addition of a solution oflithium aluminum hydride in tetrahydrofuran (a 1.0M solution, 200 ml)under ice cooling. The resulting mixture was stirred at room temperaturefor 2 hours. Water (7 ml) was then added slowly to the reaction mixture.After the termination of the reaction, a 1N aqueous potassium hydroxidesolution (7 ml) and anhydrous magnesium sulfate were successively added.After removal of the insoluble matter by filtration, the filtrate wasconcentrated under reduced pressure. The residue thus obtained waspurified by distillation under reduced pressure (1.5 mmHg, boilingpoint: 82 to 85° C.), whereby the title compound (6.10 g, 40%) wasobtained as a colorless oil.

[3736]¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.83 (2H, t, J=5.9 Hz), 2.98 (2H,t, J=5.9 Hz), 3.70 (2H, s), 3.87 (2H, br s), 8.63 (1H, s).

[3737] MS (FAB) m/z: 155 [(M+H)⁺].

Referential Example 371 Lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

[3738] In anhydrous tetrahydrofuran (200 ml),6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (6.43 g) wasdissolved, followed by the dropwise addition of a solution (1.47M, 34.00ml) of n-butyl lithium in n-hexane at an external temperature of −78° C.The resulting mixture was stirred for 40 minutes without changing thetemperature. Then a carbon dioxide gas was blown into the reactionmixture for 1 hour. After warming up to room temperature, the reactionmixture was concentrated under reduced pressure, whereby the titlecompound (9.42 g, quant.) was obtained as a pale brown foamy solid.

[3739]¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s).

[3740] MS (FAB) m/z: 199 (M+H)⁺.

Referential Example 372N-[[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]glycineEthyl Ester Trifluoroacetate

[3741] In the same manner as in Referential Example 319, an amide bondwas formed using1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine-2-carboxylicacid as a starting material, followed by deprotection usingtrifluoroacetic acid, whereby the title compound was obtained.

[3742]¹H-NMR (DMSO-d₆) δ: 1.20 (3H, t, J=7.3 Hz), 2.47-2.82 (2H, m),3.14-3.28 (1H, m), 3.30-3.39 (1H, m), 3.72-3.79 (1H, m), 3.95 (2H, d,J=5.9 Hz), 4.08-4.18 (3H, m), 4.20 (1H, dd, J=11.2, 3.4 Hz), 7.75 (1H,dd, J=8.8, 2.0 Hz), 7.84 (1H, d, J=8.8 Hz), 8.23 (1H, d, J=8.8 Hz), 8.28(1H, s), 8.30 (1H, d, J=8.8 Hz), 8.55 (1H, s), 9.29 (1H, t, J=5.9 Hz).

[3743] MS (FAB) m/z: 440 [(M+H)⁺, Cl³⁵], 442 [(M+H)⁺, Cl³⁷].

Referential Example 3731-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[[(morpholin-4-yl)carbonyl]methyl]piperazineHydrochloride

[3744] In the same manner as in Referential Example 319, an amid bondwas formed using1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineand morpholine as starting materials, followed by deprotection In thesame manner as in Referential Example 1, whereby the title compound wasobtained.

[3745]¹H-NMR (DMSO-d₆) δ: 2.65-2.91 (4H, m), 3.10-3.22 (1H, m),3.30-3.82 (12H, m), 7.74 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=8.8 Hz), 8.20(1H, d, J=8.8 Hz), 8.22-8.31 (2H, m), 8.55 (1H, s), 9.18 (1H, br s),9.32 (1H, br s).

[3746] MS (FAB) m/z: 438 [(M+H)⁺, Cl³⁵], 440 [(M+H)⁺, Cl³⁷].

Referential Example 3741-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[N-(morpholin-4-yl)carbamoyl]piperazineTrifluoroacetate

[3747] In the same manner as in Referential Example 372, the titlecompound was obtained.

[3748]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.59-3.97 (13H, m), 4.00-4.12 (1H,m), 4.38-4.50 (1H, m), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.84 (1H, d, J=8.8Hz), 8.15 (1H, d, J=8.8 Hz), 8.18 (1H, s), 8.22 (1H, d, J=8.8 Hz), 8.48(1H, s), 9.18 (1H, br s).

[3749] MS (FAB) m/z: 439 [(M+H)⁺, Cl³⁵], 441 [(M+H)⁺, Cl³⁷].

Referential Example 375 EthylN′-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]hydrazinoacetateHydrochloride

[3750] In the same manner as in Referential Example 372, the titlecompound was obtained.

[3751]¹H-NMR (DMSO-d₆) δ: 1.20-1.24 (3H, m), 2.55-2.90 (2H, m),3.00-3.20 (1H, m), 3.30-3.38 (1H, m), 3.53-3.87 (3H, m), 3.94-4.19 (3H,m), 4.27 (½H, d, J=9.8 Hz), 4.54-4.63 (½H, m), 4.95 (1H, br s), 7.75(1H, dd, J=8.8, 2.0 Hz)., 7.84-7.95 (1H, m), 8.19-8.32 (3H, m), 8.56(1H, s), 8.80-9.00 (1H, m), 9.78-10.20 (1H, m).

[3752] MS (FAB) m/z: 455 [(M+H)⁺, Cl³⁵], 457 (M+H)⁺, Cl³⁷].

Referential Example 376 4-(Aminoacetyl)morpholine Hydrochloride

[3753] In N,N-dimethylformamide (100 ml), N-tert-butoxycarbonylglycine(2.00 g), morpholine (1.00 ml), 1-hydroxybenzotriazole monohydrate (1.74g) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.84g) were dissolved, followed by stirring overnight at room temperature.After concentration under reduced pressure, the residue was diluted withdichloromethane, washed with water and dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(dichloromethane:methanol=100:1), whereby a colorless foam was obtained.The substance was dissolved in dichloromethane (2 ml), followed by theaddition of saturated solution of hydrochloride in ethanol (10 ml). Theresulting mixture was stirred at room temperature for 5 minutes. Thereaction mixture was concentrated to dryness under reduced pressure,whereby the title compound (1.80 g, quant.) was obtained as a paleyellow foam was obtained.

[3754]¹H-NMR (DMSO-d₆) δ: 3.39 (2H, t, J=4.5 Hz), 3.48 (2H, t, J=4.5Hz), 3.52-3.63 (4H, m), 3.77-3.90 (2H, m), 8.32 (3H, br s).

[3755] MS (FAB) m/z: 145 (M+H)⁺.

Referential Example 3771-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[N-[[(morpholin-4-yl)carbonyl]methyl]carbamoyl]piperazineHydrochloride

[3756] In the same manner as in Referential Example 372, the titlecompound was obtained.

[3757]¹H-NMR (DMSO-d₆) δ: 2.67 (1H, d, J=11.2 Hz), 2.79 (1H, d, J=11.2Hz), 3.09-3.18 (1H, m), 3.17-3.30 (1H, m), 3.42 (1H, d, J=13.2 Hz),3.45-3.74 (8H, m), 3.82 (1H, d, J=12.2 Hz), 4.10-4.30 (4H, m), 7.86 (1H,d, J=8.8 Hz), 7.95 (1H, d, J=8.8 Hz), 8.32 (1H, d, J=8.8 Hz), 8.40 (1H,s), 8.41 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=8.8 Hz), 8.93 (1H, br s),9.12 (1H, d, J=4.9 Hz), 10.03 (1H, br s).

[3758] MS (FAB) m/z: 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

Referential Example 3784-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazineTrifluoroacetate

[3759] In the same manner as in Referential Example 319,1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine-2-carboxylicacid was reacted with methylamine to form an amide bond and then theprotecting group was removed using trifluoroacetic acid, whereby thetitle compound was obtained.

[3760]¹H-NMR (DMSO-d₆) δ: 2.54-2.65 (2H, m), 2.67 (3H, d, J=3.9 Hz),3.12-3.22 (1H, m), 3.33 (1H, d, J=13.2 Hz), 3.70 (1H, d, J=12.2 Hz),4.04 (2H, d, J=8.8 Hz), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.87 (1H, d, J=8.8Hz), 8.20 (1H, d, J=8.8 Hz), 8.27 (1H, s), 8.29 (1H, d, J=8.8 Hz), 8.58(1H, s), 8.70 (1H, d, J=4.4 Hz), 9.06 (1H, br s).

[3761] MS (FAB) m/z: 440 [(M+H)⁺, Cl³⁵], 442 [(M+H)⁺, Cl³⁷].

[3762] In the same manner as in Referential Example 378, Compounds ofReferential Examples 379 to 384 were synthesized.

Referential Example 3794-[[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]morpholineTrifluoroacetate

[3763]¹H-NMR (DMSO-d₆) δ: 2.49-2.58 (1H, m), 2.64-2.75 (1H, m),3.09-3.81 (11H, m), 3.93 (1H, d, J=12.2 Hz), 4.76 (1H, dd, J=10.7, 2.4Hz), 7.75 (1H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8Hz), 8.27 (1H, s), 8.29 (1H, d, J=8.8 Hz), 8.58 (1H, s), 9.15 (1H, brs).

[3764] MS (FAB) m/z: 440 [(M+H)⁺, Cl³⁵], 442 [(M+H)⁺, Cl³⁷].

Referential Example 3801-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[(N-tert-butoxy)carbonyl]piperazineTrifluoroacetate

[3765]¹H-NMR (DMSO-d₆) δ: 2.58-2.70 (2H, m), 3.14-3.23 (1H, m),3.30-3.40 (1H, m), 3.64 (1H, d, J=12.2 Hz), 3.97 (1H, d, J=12.2 Hz),4.05 (1H, dd, J=10.2, 3.4 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.87 (1H,d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.27 (1H, d, J=2.0 Hz), 8.29 (1H,d, J=8.8 Hz), 8.57 (1H, s), 11.24 (1H, s).

[3766] MS (FAB) m/z: 426 [(M+H)⁺, Cl³⁵], 428 [(M+H)⁺, Cl³⁷].

Referential Example 3811-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[(N-isopropyl)carbamoyl]piperazineHydrochloride

[3767]¹H-NMR DMSO-d₆) δ: 1.05-1.18 (6H, m), 2.60-2.77 (2H, m), 3.08-3.16(1H, m), 3.30-3.41 (1H, m), 3.67 (1H, d, J=12.2 Hz), 3.80-3.90 (1H, m),4.99 (2H, d, J=7.8 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.87 (1H, dd,J=8.8, 1.5 Hz), 8.22 (1H, d, J=8.8 Hz), 8.28 (1H, s), 8.31 (1H, d, J=8.8Hz), 8.58 (1H, s), 8.74 (1H, d, J=7.3 Hz).

[3768] MS (FAB) m/z: 396 [(M+H)⁺, Cl³⁵], 398 [(M+H)⁺, Cl³⁷].

Referential Example 3821-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[[(piperidin-1-yl]carbonyl]methyl]piperazineHydrochloride

[3769]¹H-NMR (DMSO-d₆) δ: 1.45-1.90 (8H, m), 2.78 (1H, d, J=16.1 Hz),3.08-3.20 (1H, m), 3.20-3.60 (7H, m), 3.68-3.92 (3H, m), 7.58 (1H, d,J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz), 7.85-7.98 (3H, m), 8.31 (1H, s), 9.09(1H, br s), 11.32 (1H, br s).

[3770] MS (FAB) m/z: 436 [(M+H)⁺, Cl³⁵], 438 [(M+H)⁺, Cl³⁷].

Referential Example 3831-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[[N-(2-methoxybenzyl)]carbamoyl]piperazineHydrochloride

[3771]¹H-NMR (DMSO-d₆) δ: 2.69 (1H, t, J=11.2 Hz), 2.72-2.30 (1H, m),3.08-3.16 (1H, m), 3.31-3.37 (1H, m), 3.68 (1H, d, J=12.2 Hz), 4.05 (1H,d, J=12.2 Hz), 4.14 (1H, dd, J=10.3, 3.4 Hz), 4.29 (1H, d, J=5.4 Hz),6.93 (1H, t, J=7.3 Hz), 7.02 (1H, d, J=7.8 Hz), 7.24 (1H, d, J=7.3 Hz),7.29 (1H, t, J=7.8 Hz), 7.77 (1H, dd, J=8.8, 2.0 Hz), 7.88 (1H, d, J=8.8Hz), 8.23 (1H, d, J=8.8 Hz), 8.30 (1H, s), 8.32 (1H, d, J=8.8 Hz), 8.59(1H, s), 9.17 (1H, t, J=5.4 Hz).

[3772] MS (FAB) m/z: 474 [(M+H)⁺, Cl³⁵], 476 [(M+H)⁺, Cl³⁷].

Referential Example 3844-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)]carbamoyl]piperazine

[3773]¹H-NMR (DMSO-d₆) δ: 2.54-2.75 (2H, m), 3.02-3.51 (7H, m), 3.70(1H, d, J=12.2 Hz), 7.75 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=8.8 Hz), 8.22(1H, d, J=8.8 Hz), 8.28 (1H, s), 8.31 (1H, d, J=8.8 Hz), 8.58 (1H, s),8.97 (1H, t, J=5.4 Hz), 10.01 (1H, br s).

[3774] MS (FAB) m/z: 412 [(M+H)⁺, Cl³⁵], 414 [(M+H)⁺, Cl³⁷].

Referential Example 3851-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[carbamoylmethyl]piperazineHydrochloride

[3775] In N,N-dimethylformamide (20 ml),1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(800 mg) was dissolved, followed by the addition of pyridine (0.85 ml),ammonium bicarbonate (417 mg) and di-tert-butoxy carbonate (1.15 g). Theresulting mixture was stirred at room temperature for 7 hours. Afterconcentration of the reaction mixture under reduced pressure, theresidue was added with dichloromethane, washed with 1N hydrochloric acidand a saturated aqueous solution of sodium bicarbonate, each once andthen dried over anhydrous sodium sulfate. The solvent was then distilledoff under reduced pressure. After the addition of saturated aqueoushydrochloric acid in ethanol (30 ml) to the residue, the resultingmixture was concentrated under reduced pressure. While washing withethanol, the solid thus precipitated was removed by filtration. Thefiltrate was then concentrated under reduced pressure. The residue wascrystallized in methanol, whereby the title compound (426 mg) wasobtained as a colorless solid.

[3776] IR(KBr)cm⁻¹: 3185, 2917, 2684, 2607, 1677, 1342, 1299, 1170,1155, 1135, 755, 692, 578.

[3777] H-NMR (DMSO-d₆) δ: 2.58-2.65 (1H, m), 2.72-2.83 (1H, m),3.12-3.21 (1H, m), 3.30-3.48 (3H, m), 3.55-3.81 (1H, m), 7.21 (1H, brs), 7.66 (1H, br s), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.85 (1H, d, J=8.8Hz), 8.20 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.29 (1H, d, J=8.8 Hz), 8.56(1H, s), 9.02-9.23 (2H, m).

[3778] MS (FAB) m/z: 368 [(M+H)⁺, Cl³⁵], 370 [(M+H)⁺, Cl³⁷].

Referential Example 386 1-(3-Furyl)-2-nitroethylene

[3779] To a solution of 3-furaldehyde (10.0 g) in ethanol (200 ml),nitromethane (6.37 g) was added at room temperature, followed by thedropwise addition of a 10N-aqueous sodium hydroxide solution (11.0 ml)at 0° C. The resulting mixture was stirred for 1 hour. The reactionmixture was poured into a 15% aqueous solution of hydrochloric acid (500ml). The precipitate so formed was collected by filtration and dried,whereby the title compound (8.01 g) was obtained as a yellowish whitesolid.

[3780]¹H-NMR (CDCl₃) δ: 6.57 (1H, d, J=2.0 Hz), 7.39 (1H, d, J=13.4 Hz),7.52 (1H, br s), 7.83 (1H, br s), 7.94 (1H, d, J=13.4 Hz).

Referential Example 387 2-(t-Butoxycarbonylamino)-1-[(3-furyl)ethane

[3781] In tetrahydrofuran (170 ml), lithium aluminum hydride (2.20 g)was suspended, followed by the dropwise addition of a solution of1-(3-furyl)-3-nitroethylene (8.00 g) in tetrahydrofuran (80 ml) at roomtemperature over 2 hours. The resulting mixture was stirred for 30minutes. After the reaction mixture was cooled to 0° C., ethyl acetate(50 ml) and then water (10 m) were dropwise added thereto. The mixturewas stirred while gradually warmed up. The reaction mixture wassubjected to Celite filtration by using ethyl acetate. After thefiltrate was concentrated, the residue was dissolved in methylenechloride (200 ml). Di-t-butyl dicarbonate (12.6 g) was added to theresulting solution at room temperature and the mixture was stirred for 1hour. The reaction mixture was concentrated and the residue was purifiedby chromatography on a silica gel column (400 g of silica gel,hexane:ethyl acetate=15:1→8:1), whereby the title compound (4.30 g) wasobtained as a pale yellow transparent oil.

[3782]¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.61 (2H, t, J=6.8 Hz), 3.25-3.37(2H, m), 4.57 (1H, br s), 6.29 (1H, s), 7.26 (1H, s), 7.37 (1H, s).

Referential Example 3886-(t-Butoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine

[3783] Paraformaldehyde (625 mg) and p-toluenesulfonic acid (49.5 mg)were added to a solution of 2-(t-butoxycarbonylamino)-1-(3-furyl)ethane(2.20 g) in toluene (300 ml), followed by heating under reflux for 2hours while dehydrating using a Dean Stark apparatus. After the reactionmixture was allowed to cool down to room temperature, a saturatedaqueous solution (200 ml) of sodium bicarbonate and ethyl acetate (200ml) were added to the reaction mixture to cause separation. The waterlayer was extracted with ethyl acetate (100 ml). The organic layers werecombined, washed with saturated aqueous NaCl solution (100 ml), driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column (100 gof silica gel, hexane:ethyl acetate=15:1→10:1), whereby the titlecompound (1.04 g) was obtained as a white solid.

[3784] IR(KBr) cm⁻¹:

[3785] 3145, 3005, 2976, 2925, 2862, 1695, 1448, 1419, 1365, 1279, 1228,1165, 1124, 912, 895, 758.

[3786]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.52 (2H, br s), 3.63 (2H, br s),4.44 (2H, s), 6.25 (1H, s), 7.29 (1H, s).

[3787] MS (FAB) m/z: 224 [(M+H)⁺], 168 [(M+H-isobutene(56))⁺].

Referential Example 389 6-Methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine

[3788] To 6-(t-butoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine(1.05 g), a saturated solution of hydrochloride in ethanol (30 ml) wasadded at room temperature. After stirring for 2 hours, the reactionmixture was concentrated. The residue thus obtained was suspended inmethylene chloride (20 ml), followed by the addition of methanol (20ml), triethylamine (1.31 ml), acetic acid (810 μl), formaldehyde (a 37%aqueous solution, 610 μl) and sodium triacetoxyborohydride (1.51 g) atroom temperature. The resulting mixture was stirred for 1 hour. To thereaction mixture, a saturated aqueous solution (100 ml) of sodiumbicarbonate and methylene chloride (20 ml) were added to causeseparation. The water layer was extracted with methylene chloride (3×10ml). The organic layers were combined, dried over anhydrous sodiumsulfate-and concentrated under reduced pressure. The residue thusobtained was purified by chromatography on a silica gel column (50 g ofsilica gel, methylene chloride:acetone=1:1→1:2→methylenechloride:methanol=10:1), whereby the title compound (434 mg) wasobtained as a colorless transparent oil.

[3789]¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 2.56 (2H, t, J=5.6 Hz), 2.67 (2H,t, J=5.6 Hz), 3.48 (2H, s), 6.23 (1H, d, J=2.0 Hz), 7.25 (1H, s).

Referential Example 390 3-Aminoacrylaldehyde

[3790] To a solution of isoxazole (5.00 g) in methanol (100 ml), Raneynickel (“R-100”, product of Nikko Chemical) (about 1.0 g) was added atroom temperature. Under a hydrogen atmosphere (3.05-2.65 kg/cm²), theresulting mixture was stirred for 3 hours. The reaction mixture wassubjected to Celite filtration and the filtrate was concentrated. Theresidue thus obtained was reprecipitated in a chloroform—hexane system,whereby the title compound (4.91 g, 69.1 mmol, 95%) was obtained as ayellow solid.

[3791]¹H-NMR (CDCl₃) δ: 4.60-5.20 (2H, br), 5.45 (1H, dd, J=12.7, 8.3Hz), 7.15 (1H, d, J=12.7 Hz), 9.18 (1H, d, J=8.3 Hz).

[3792]¹H-NMR (CD₃OD) δ: 5.55 (1H, dd, J=12.2, 9.3 Hz), 7.59 (1H, d,J=12.2 Hz), 8.98 (1H, d, J=9.3 Hz).

Referential Example 3916-(t-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthylidine

[3793] Triethylamine (1.50 ml) and pyridinium acetate (30.0 mg) wereadded to 1-benzyl-4-piperidone (3.80 g) and 3-aminoacrylaldehyde (2.10g), followed by stirring under heat at 120° C. After 22 hours, thereaction mixture was allowed to cool down to room temperature and thebrown caramel-like substance thus obtained was dissolved in a 3N aqueoussolution of hydrochloric acid. The resulting solution was extracted withchloroform (2×50 ml). To the water layer, a saturated aqueous solution(50 ml) of sodium bicarbonate was added, followed by extraction withchloroform (3×60 ml). The organic layer was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was distilled (0.90 mmHg, 145 to 150° C.), whereby about 3:2mixture (1.98 g) of 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthylidine in theform of a pale yellow transparent oil and 1-benzyl-4-piperidone as thestarting material was obtained.

[3794] The mixture was dissolved in acetic acid (25 ml). To theresulting solution, 10% palladium-carbon (500 mg) was added, followed byvigorous stirring at 50 to 60° C. under a hydrogen atmosphere (about 1atm). After the stirring was continued for 2 hours, the reaction mixturewas allowed to cool down and filtered. By the concentration of thefiltrate, a residue containing 5,6,7,8-tetrahydro-1,6-naphthylidine inthe form of a colorless transparent oil was obtained.

[3795] The residue was dissolved in toluene (20 ml), followed by theaddition of a 40% aqueous solution of sodium hydroxide (30 ml) anddi-t-butyl dicarbonate (3.20 g, 14.7 mmol) at room temperature. Afterstirring for 10 minutes, water (30 ml) and toluene (20 ml) were added tothe reaction mixture to cause separation. The water layer was extractedwith toluene (30 ml). The organic layers were combined, washed withsaturated aqueous NaCl solution (50 ml), dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column (50 g ofsilica gel, methylene chloride:ethyl acetate=5:1→3:1), whereby the titlecompound (981 mg) was obtained as a colorless transparent oil.

[3796] IR(KBr)cm⁻¹: 2974, 1693, 1577, 1454, 1419, 1392, 1365, 1288,1259, 1241, 1228, 1161, 1119, 1097, 989, 930, 881, 862, 789, 768, 737.

[3797]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.01 (2H, t, J=5.9 Hz), 3.76 (2H,t, J=5.9 Hz), 4.59 (2H, s), 7.13 (1H, dd, J=7.8, 4.9 Hz), 7.41 (1H, d,J=7.8 Hz), 8.43 (1H, d, J=4.9 Hz).

[3798] MS (FAB) m/z: 235 [(M+H)⁺], 179 [(M+H)⁺-isobutene(56)].

Referential Example 3926-(t-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthylidin-1-oxide

[3799] To a solution of6-(t-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthylidine (1.72 g) inmethylene chloride (40 ml), metachloroperbenzoic acid (3.80 g) was addedat 0° C. and the resulting mixture was stirred. Thirty minutes later,dimethyl sulfide (1.62 ml) was added to the reaction mixture, followedby stirring at room temperature for 30 minutes. To the reaction mixture,a saturated aqueous solution (150 ml) of sodium bicarbonate andmethylene chloride (30 ml) were added to cause separation. The waterlayer was extracted with methylene chloride (3×30 ml). The organiclayers were combined, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue thus obtainedwas purified by chromatography on a silica gel column (100 g of silicagel, methylene chloride:methanol=20:1→10:1), whereby the title compound(1.80 g, 7.19 mmol, 98%) was obtained as a colorless transparent oil.

[3800] IR(KBr)cm⁻¹: 2976, 2929, 2860, 1697, 1431, 1365, 1263, 1240,1167, 1115, 1028, 910, 771.

[3801]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.05 (2H, t, J=5.9 Hz), 3.75 (2H,t, J=5.9 Hz), 4.59 (2H, s), 7.04 (1H, d, J=8.8 Hz), 7.14 (1H, dd, J=8.8,5.9 Hz), 8.18 (1H, d, J=5.9 Hz).

Referential Example 3936-(t-Butoxycarbonyl)-2-cyano-5,6,7,8-tetrahydro-1,6-naphthylidine

[3802] To a solution of6-(t-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthylidin-1-oxide (760mg) in methylene chloride (15 ml), trimethylsilyl cyanide (610 μl) wasadded at room temperature and the resulting mixture was stirred for 5minutes. To the reaction mixture, N,N-dimethylcarbamoyl chloride (420μl) was added, followed by stirring for 41 hours. To the reactionmixture, a saturated aqueous solution (50 ml) of sodium bicarbonate andchloroform (30 ml) were added to cause separation. The water layer wasextracted with chloroform (30 ml). The organic layers were combined,dried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue thus obtained was purified bychromatography on a silica gel column (50 g of silica gel, methylenechloride:ethyl acetate=6:1→2:1), whereby the title compound (697 mg) wasobtained as a white solid. The resulting white solid was recrystallizedfrom a hexane—methylene chloride system, whereby colorless needle-likecrystals were obtained.

[3803] IR(KBr)cm⁻¹: 2978, 2933, 2235, 1693, 1685, 1572, 1477, 1458,1415, 1365, 1267, 1238, 1169, 1161, 1124, 1097, 935, 839, 768.

[3804]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.05 (2H, t, J=5.9 Hz), 3.77 (2H,t, J=5.9 Hz), 4.67 (2H, s), 7.54 (2H, s).

[3805] MS (FAB) m/z: 260 [(M+H)⁺], 204 [(M+H)⁺-isobutene(56)].

[3806] Elementary analysis for C₁₄H₁₇N₃O₂

[3807] Calculated: C, 64.85; H, 6.61; N, 16.20.

[3808] Found: C, 64.89; H, 6.60; N, 16.57.

Referential Example 3946-(t-Butoxycarbonyl)-2-methoxycarbonyl-5,6,7,8-tetrahydro-1,6-naphthylidine

[3809] To a solution of6-(t-butoxycarbonyl)-2-cyano-5,6,7,8-tetrahydro-1,6-naphthylidine (1.25g) in methanol (40 ml), concentrated hydrochloric acid (40 ml) was addedat room temperature and the resulting mixture was stirred at 100° C. for3 hours. After the reaction mixture was allowed to cool down to roomtemperature, it was gradually poured into tetrahydrofuran (150 ml) andan aqueous solution (250 ml) of sodium carbonate (40 g), which had beenstirred in advance, followed by the addition of di-t-butyl dicarbonate(1.58 g, 7.23 mmol) at room temperature. The resulting mixture wasstirred for 30 minutes. Water (200 ml) was added to the reaction mixtureto cause separation. The water layer was extracted with ethyl acetate(100 ml). The organic layers were combined, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue so obtained was purified by chromatography on a silica gelcolumn (100 g of silica gel, methylene chloride:ethyl acetate=3:1→1:1),whereby the title compound (955 mg) was obtained as a colorless oil.

[3810]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.12 (2H, t, J=5.9 Hz), 3.77 (2H,t, J=5.9 Hz), 4.00 (3H, s), 4.67 (2H, s), 7.57 (1H, d, J=8.1 Hz), 7.98(1H, d, J=8.1 Hz).

Referential Example 3956-(t-Butoxycarbonyl)-2-[[4-(chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5,6,7,8-tetrahydro-1,6-naphthylidine

[3811] To a solution of6-(t-butoxycarbonyl)-2-methoxycarbonyl-5,6,7,8-tetrahydro-1,6-naphthylidine(955 mg) in tetrahydrofuran (20 ml), a 3N aqueous solution of sodiumhydroxide (20 ml) was added at room temperature. After stirring for 2hours, ammonium sulfate (16.0 g) was added to the reaction mixture.Concentrated hydrochloric acid was added to adjust its pH to 4, followedby extraction with chloroform (2×20 ml). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure,whereby the residue (874 mg), that is,6-(t-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthylidine-2-carboxylicacid was obtained as a white solid. To a solution of the resultingresidue in N,N-dimethylformamide (40 ml), methylene chloride (40 ml) and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (1.42 g)were dissolved, followed by the addition of1-(dimethylaminopropyl)-3-ethylcarbodiimide (785 mg) and1-hydroxybenzotriazole (555 mg) at room temperature. Then,diisopropylethylamine (1.71 ml) was added at 0° C. After stirringovernight at room temperature, a 10% aqueous solution of citric acid(200 ml) and methylene chloride (100 ml) were added to the reactionmixture to cause separation. The organic layer was extracted withmethylene chloride (50 ml). The organic layers were combined, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (100 g ofsilica gel, methylene chloride:acetone=10:1→5:1). The white solid thusobtained was reprecipitated in a methylene chloride—methanol—watersystem. After filtration and washing with water, the title compound(1.44 g) was obtained as a white solid.

[3812] IR(KBr)cm⁻¹: 2978, 2924, 2846, 1697, 1637, 1577, 1479, 1454,1432, 1365, 1340, 1238, 1166, 733, 577.

[3813]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.92 (2H, t, J=5.7 Hz), 3.11 (2H,br t, J=4.4 Hz), 3.23 (2H, br t, J=4.4 Hz), 3.74 (2H, t, J=5.7 Hz), 3.78(2H, br t, J=4.4 Hz), 3.90 (2H, br t, J=4.4 Hz), 4.59 (2H, s), 7.42 (1H,br d, J=7.8 Hz), 7.47 (1H, br d, J=7.8 Hz), 7.58 (1H, dd, J=2.0, 8.8Hz), 7.77 (1H, dd, J=2.0, 8.5 Hz), 7.90 (1H, d, J=2.0 Hz), 7.92-7.95(2H, m), 8.30 (1H, br s).

[3814] MS (FAB) m/z: 571 [(M+H)⁺, Cl³⁵], 515 [(M+H)⁺-isobutene(56),Cl³⁵].

[3815] Elementary analysis for C₂₈H₃₁ClN₄O₅S

[3816] Calculated: C, 58.89; H, 5.47; N, 9.81; Cl, 6.21; S, 5.61.

[3817] Found: C, 58.59; H, 5.61; N, 9.84; Cl, 6.53; S, 5.66.

Referential Example 3962-(t-Butoxycarbonylamino)-3-(t-butyldiphenylsiloxy)propanol

[3818] At room temperature, imidazole (6.43 g) was added to a solutionof N-(t-butoxycarbonyl)-L-serine methyl ester (13.8 g) inN,N-dimethylformamide (140 ml), followed by the addition oft-butyldiphenylsilyl chloride (19.7 ml) at 0° C. The resulting mixturewas stirred at room temperature for 39 hours. Ethyl acetate (200 ml) andwater (600 ml) were added to the reaction mixture to cause separation.The water layer was extracted with ethyl acetate (100 ml). The organiclayers were combined, washed with saturated aqueous NaCl solution (100ml), dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue thus obtained was dissolved in tetrahydrofuran(100 ml) and methanol (100 ml) without purification, followed by theaddition of sodium borohydride (7.20 g) in portions at 0° C. Afterstirring at 0° C. for 2 hours and then at room temperature for 1 hour,ethyl acetate (100 ml), an aqueous saturated solution of ammoniumchloride (300 ml) and water (300 ml) were added to the reaction mixtureto cause separation. The water layer was extracted with ethyl acetate(100 ml). The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue thusobtained was purified by chromatography on a silica gel column (500 g ofsilica gel, hexane:ethyl acetate=10:1→1:1), whereby the title compound(24.9 g) was obtained as a white solid.

[3819]¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.44 (9H, s), 2.39 (1H, br s),3.63-3.85 (5H, m), 5.07 (1H, br s), 7.35-7.48 (6H, m), 7.60-7.67 (4H,m).

Referential Example 3972-(t-Butoxycarbonylamino)-3-(t-butyldiphenylsiloxy)propanal

[3820] To a solution of2-(t-butoxycarbonylamino)-3-(t-butyldiphenylsiloxy)propanol (3.03 g) inmethylene chloride (100 ml), Dess-Martin periodinane (3.60 g) was addedat room temperature. The resulting mixture was stirred for 30 minutes.To the reaction mixture, a saturated aqueous solution (50 ml) of sodiumbicarbonate and a 10% aqueous solution (50 ml) of sodium sulfite wereadded to cause separation. The water layer was extracted with diethylether (50 ml). The organic layers were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue thusobtained was purified by chromatography on a silica gel column (150 g ofsilica gel, hexane:ethyl acetate=4:1→3:1), whereby the title compound(2.97 g) was obtained as a colorless transparent oil.

[3821]¹H-NMR (CDCl₃) δ: 1.03 (9H, s), 1.46 (9H, s), 3.93 (1H, dd, J=3.9,10.3 Hz), 4.18 (1H, d, J=2.9, 10.3 Hz), 4.27-4.35 (1H, m), 5.33-5.43(1H, m), 7.32-7.48 (6H, m), 7.55-7.63 (4H, m), 9.66 (1H, s)

Referential Example 3981,5-Bis(t-butoxycarbonyl)-2-(t-butyldiphenylsiloxy)methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

[3822] To a solution of diisopropylamine (2.35 ml) in tetrahydrofuran(40 ml), n-butyl lithium (a 1.66 N hexane solution, 9.20 ml) was addedat 0° C., followed by stirring for 30 minutes. To the reaction mixture,a solution of N-(t-butoxycarbonyl)-4-piperidone (2.77 g) intetrahydrofuran (10 ml) was added at −78° C., and the mixture wasstirred for 1.5 hours. To the reaction mixture, a solution of2-(t-butoxycarbonylamino)-3-(t-butyldiphenylsiloxy)propanal (2.97 g) intetrahydrofuran (10 ml) which had been cooled to −78° C. was addeddropwise. The mixture was warmed up gradually and stirred for 13 hours.Water (150 ml) and diethyl ether (350 ml) were added to the reactionmixture to cause separation. The water layer was extracted with diethylether (100 ml). The organic layers were combined, washed with water (100ml) and saturated aqueous NaCl solution (3×100 ml), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue thusobtained was dissolved in methylene chloride (20 ml). Concentratedhydrochloric acid was added dropwise and the mixture was adjusted to pH5, followed by stirring for 1 hour. Concentrated hydrochloric acid wasfurther added dropwise to adjust its pH to 4, followed by stirring for 1hour. A saturated aqueous solution (50 ml) of sodium bicarbonate andmethylene chloride (20 ml) were added to cause separation. The waterlayer was extracted with diethyl ether (2×50 ml). The organic layerswere combined, washed with saturated aqueous NaCl solution (50 ml),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue thus obtained was purified by chromatography on asilica gel column (150 g of silica gel, hexane:ethyl acetate=8:1→4:1),whereby the title compound (2.20 g) was obtained as a colorlesstransparent caramel-like substance.

[3823] IR(KBr)cm⁻¹: 2931, 2856, 1738, 1697, 1473, 1427, 1392, 1367,1350, 1331, 1232, 1167, 1144, 1109, 1066, 822, 739.

[3824]¹H-NMR (CDCl₃) δ: 1.08 (9H, s), 1.43 (9H, s), 1.49 (9H, s), 2.89(2H, br s), 3.64 (2H, br s), 4.32 (2H, s), 4.85 (2H, br s), 6.12 (1H,s), 7.30-7.48 (6H, m), 7.60-7.75 (4H, m).

[3825] MS(FAB/m-NBA/NaCl) m/z: 613[(M+Na)⁺].

Referential Example 3991,5-Bis(t-butoxycarbonyl)-2-hydroxymethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

[3826] To a solution of1,5-bis(t-butoxycarbonyl)-2-(t-butyldiphenylsiloxy)methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(2.10 g) in pyridine (20 ml), a mixture of hydrogen fluoride andpyridine was added at 0° C., followed by stirring at room temperaturefor 1 hour. After the reaction mixture was poured into ethyl acetate (50ml) and ice water (300 ml) which had been stirred in advance, theresulting mixture was separated. The water layer was extracted withethyl acetate (50 ml). The organic layers were combined, washed with asaturated aqueous solution of sodium bicarbonate, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue thusobtained was purified by chromatography on a silica gel column (150 g ofsilica gel, hexane:ethyl acetate=3:1), whereby the title compound (882mg) was obtained as a colorless, transparent caramel-like substance.

[3827] IR(KBr)cm⁻¹: 3432, 2976, 2931, 1736, 1695, 1419, 1365, 1350,1323, 1234, 1167, 1144, 1105, 754.

[3828]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.60 (9H, s), 2.85 (2H, br s),3.45-3.70 (1H, br), 3.64 (2H, br s), 4.29 (2H, s), 4.59 (2H, d, J=7.3Hz), 6.01 (1H, s).

[3829] MS (FAB/m-NBA/NaCl) m/z: 375 [(M+Na)⁺].

Referential Example 4001,5-Bis(t-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

[3830] To a solution of1,5-bis(t-butoxycarbonyl)-2-hydroxymethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(14.0 mg) in methylene chloride (2.0 ml), Dess-Martin periodinane (34.0mg) was added at room temperature. The resulting mixture was stirred for1 hour. To the reaction mixture, ethyl acetate (10 ml), a 10% aqueoussolution (10 ml) of sodium thiosulfate and an aqueous solution (10 ml)of sodium bicarbonate were added to cause separation. The water layerwas extracted with ethyl acetate (10 ml). The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue thus obtained was purified by thin-layerpreparative chromatography on silica gel (hexane:ethyl acetate=2:1),whereby the title compound (9.8 mg) was obtained as a colorlesstransparent caramel-like substance.

[3831] IR(KBr)cm⁻¹: 2976, 2933, 1741, 1697, 1660, 1479, 1413, 1367,1346, 1298, 1281, 1234, 1165, 1146, 1103, 895, 850, 768.

[3832]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.63 (9H, s), 2.96 (2H, br t,J=5.4 Hz), 3.68 (2H, br t, J=5.4 Hz), 4.37 (2H, s), 6.97 (1H, s), 10.14(1H, br s).

[3833] MS (FAB/m-NBA) m/z: 351 [(M+H)⁺], 295 [(M+H−isobutene(56))⁺], 239[(M+H)−2×isobutene (56))⁺].

Referential Example 4011,5-Bis(t-butoxycarbonyl)-2-[[4-(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

[3834] To a solution of1,5-bis(t-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(44.0 mg) in t-butanol (2.0 ml), 2-methyl-2-butene (150 μl) and anaqueous solution (6.0 ml) of sodium chlorite (102 mg) and sodiumdihydrogenphosphate (135 mg) were added at room temperature. Afterstirring for 21 hours, the reaction mixture was added with diethyl ether(10 ml) and water (10 ml), followed by the addition of ammonium sulfateuntil saturation. The resulting mixture was separated, followed byextraction with diethyl ether (10 ml). The organic layers were combined,dried over anhydrous sodium sulfate and concentrated under reducedpressure, whereby the residue, that is,1,5-bis(t-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylicacid was obtained as a white foamy substance. To a solution of theresulting residue in N,N-dimethylformamide (2.0 ml), methylene chloride(2.0 ml) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride (55.0 mg) were dissolved, followed by the addition of1-(dimethylaminopropyl)-3-ethyl carbodiimide (30.5 mg) and1-hydroxybenzotriazole (21.5 mg) at room temperature. At 0° C.,diisopropylethylamine (67.0 μl) was added thereto. After stirringovernight at room temperature, a 10% aqueous citric acid solution (10ml) and methylene chloride (10 ml) were added to the reaction mixture tocause separation. The organic layer was extracted with methylenechloride (10 ml). The organic layers were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure. The resultingresidue was purified by thin-layer preparative chromatography on silicagel (methylene chloride:acetone=10:1) and the white solid thus obtainedwas reprecipitated in a methylene chloride—methanol—water system. Afterfiltration and washing with water, the title compound (50.0 mg) wasobtained as a colorless transparent caramel-like substance.

[3835] IR(KBr)cm⁻¹: 2981, 2929, 2860, 1743, 1693, 1647, 1456, 1421,1367, 1348, 1325, 1279, 1236, 1165, 1103, 955, 945, 729.

[3836]¹H-NMR (CDCl₃) δ: 1.32 (9H, s), 1.46 (9H, s), 2.83 (2H, br t,J=5.6 Hz), 3.04 (2H, br), 3.17 (2H, br), 3.55 (2H, br), 3.62 (2H, br t,J=5.6 Hz), 3.82 (2H, br), 4.25 (2H, s), 5.94 (1H, s), 7.59 (1H, dd,J=2.0, 8.8 Hz), 7.76 (1H, dd, J=1.7, 8.5 Hz), 7.87-7.98 (3H, m), 8.30(1H, br s).

[3837] MS (FAB/m-NBA/NaCl) m/z: 681 [(M+Na)⁺], 581 [(M+Na−Boc(100))⁺],525 [(M+Na-Boc(100)-isobutene(56))⁺].

Referential Example 4021-(tert-Butoxycarbonyl)-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[3838] To a solution of lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (293mg) in N,N-dimethylformamide (10 ml) were added1-(tert-butoxycarbonyl)piperazine (294 mg), 1-hydroxybenzotriazolemonohydrate (214 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (303 mg) at room temperature. After stirring for 38 hours,methylene chloride (20 ml) and water (200 ml) were added to the reactionmixture to separate it into layers. The water layer thus obtained wasextracted with methylene chloride (3×10 ml). The organic layers werecombined, washed with a saturated aqueous solution (100 ml) of sodiumbicarbonate, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (methylene chloride:acetone=2:1),whereby the title compound (300 mg) was obtained as a pale yellowviscous substance.

[3839]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.51 (3H, s), 2.83 (2H, t, J=5.7Hz), 2.94 (2H, t, J=5.7 Hz), 3.53 (4H, t, J=5.2 Hz), 3.71 (2H, s), 3.75(2H, br s), 4.38 (2H, br s).

[3840] MS (FAB) m/z: 367 (M+H)⁺, 311 (M-isobutene+H)⁺, 267 (M−Boc+H)⁺.

Referential Example 403 Thiazolo[4,5-c]pyridine

[3841] In formic acid (60 ml) was dissolved3-(tert-butoxyamino)-4-mercaptopyridine (9.20 g), followed by heatingunder reflux for 4 hours. After the reaction mixture was concentratedunder reduced pressure and a 5N aqueous solution (100 ml) of potassiumhydroxide was added to the residue, the resulting mixture was extractedwith ether. The organic layer was dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. Diethylether was added to the residue and the solid so precipitated wascollected by filtration, whereby the title compound was obtained as acolorless solid (3.97 g).

[3842]¹H-NMR (CDCl₃) δ: 7.93 (1H, d, J=5.4 Hz), 8.60 (1H, d, J=5.4 Hz),9.07 (1H, s), 9.46 (1H, s).

Referential Example 4045-Methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine

[3843] In N,N-dimethylformamide (80 ml) was dissolvedthiazolo[4,5-c]pyridine (700 mg), followed by the addition of methyliodide (0.65 ml). The resulting mixture was stirred under heat at 80° C.for 4 hours. After concentration of the reaction mixture under reducedpressure, the residue was dissolved in water (100 ml). Sodiumborohydride (583 mg) was added to the resulting solution, followed bystirring at room temperature for 1 hour. After the addition of asaturated aqueous solution of potassium carbonate, the resulting mixturewas extracted with ether. The organic layer thus extracted was driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was purified by chromatography on asilica gel column (methylene chloride:methanol=25:1), whereby the titlecompound (596 mg) was obtained as a colorless oil.

[3844]¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.77 (2H, t, J=5.4 Hz), 2.92-3.00(2H, m), 3.69 (2H, t, J=2.0 Hz), 8.61 (1H, s).

[3845] MS (FAB) m/z: 155 (M+H)⁺.

Referential Example 405 Lithium5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylate

[3846] In anhydrous tetrahydrofuran (10 ml) was dissolved5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine (583 mg), followed bythe dropwise addition of a hexane solution (1.54M, 2.70 ml) of n-butyllithium at −78° C. After stirring for 10 minutes, the reaction mixturewas warmed up to 0° C. and stirring was conducted for 30 minutes. Thereaction mixture was cooled to −78° C. A carbon dioxide gas was blowninto the reaction mixture for 15 minutes, followed by warming up to roomtemperature. The reaction mixture was concentrated under reducedpressure, whereby the title compound (820 mg) was obtained as a palebrown foamy solid.

[3847]¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.64 (2H, br s), 2.80 (2H, brs), 3.44 (2H, br s).

[3848] MS (FD) m/z: 199 (M+H)⁺.

Referential Example 406 Lithium thiazolo[4,5-c]pyridine-2-carboxylate

[3849] In the same manner as in Referential Example 405, the titlecompound was obtained.

[3850]¹H-NMR (DMSO-d₆) δ: 8.07 (1H, d, J=5.4 Hz), 8.48 (1H, d, J=5.4Hz), 9.22 (1H, s).

Referential Example 4075-Isopropyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine

[3851] In the same manner as in Referential Example 404, the titlecompound was obtained.

[3852]¹H-NMR (CDCl₃) δ: 1.16 (6H, d, J=6.8 Hz), 2.80-2.92 (4H, m),2.95-3.03 (1H, m), 3.83 (2H, t, J=2.0 Hz), 8.60 (1H, s).

[3853] MS (FAB) m/z: 183 (M+H)⁺.

Referential Example 408 Lithium5-isopropyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylate

[3854] In the same manner as in Referential Example 405, the titlecompound was obtained.

[3855]¹H-NMR (DMSO-d₆) δ: 2.64 (2H, br s), 2.80 (2H, br s), 3.44 (2H, brs).

[3856] MS (FAB) m/z: 277 (M+H)⁺.

Referential Example 409 1-Benzoyl-3-bromo-2-methyl-4-piperidone

[3857] In diethyl ether (50 ml) was suspended copper cyanide (197 mg),followed by the dropwise addition of a diethyl ether solution (1.10mole, 4.00 ml) of methyl lithium at −78° C. The reaction mixture waswarmed up to 0° C. After the reaction mixture was stirred for 10minutes, it was cooled to −78° C. again. To the reaction mixture wasadded dropwise a diethyl ether solution (5 ml) ofN-benzoylazacyclohexa-2-en-4-one (400 mg) (Can. J. Chem., 1981,3136-3140) at −78° C., followed by stirring for 30 minutes. Aftertrimethylsilyl chloride (0.53 ml, 4.20 mmol) was added dropwise to thereaction mixture, the resulting mixture was warmed up to roomtemperature. The reaction mixture was added with a saturated aqueoussolution of sodium bicarbonate. The resulting solution was thenextracted with ethyl acetate. The organic layer thus extracted waswashed with aqueous NaCl solution. The extract was dried over anhydroussodium sulfate and distilled to remove the solvent. The residue wasdissolved in acetone (10 ml), followed by the addition of sodium acetate(135 mg), water (2 ml) and N-bromosuccinic imide (292 mg) under icecooling. The resulting mixture was stirred overnight at roomtemperature. To the reaction mixture was added an aqueous solution ofsodium thiosulfate (2 moles, 10 ml). After stirring for 30 minutes,ethyl acetate was added and the organic layer was collected. The organiclayer thus obtained was washed with saturated aqueous NaCl solution,dried over anhydrous sodium sulfate and distilled to remove the solvent.The residue was purified by chromatography on a silica gel column (ethylacetate:hexane=1:3), whereby the title compound (240 mg) was obtained asa yellow oil.

[3858]¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=7.3 Hz), 2.20-2.40 (1H, m), 2.65(1H, br s), 3.18-3.58 (2H, m), 4.01 (1H, br s), 4.15-4.62 (½H, m),4.80-5.28 (½H, m), 7.40-7.55 (5H, m).

[3859] MS (FAB) m/z: 296 (M⁺, Br⁷⁹), 298 (M⁺, Br⁸¹).

Referential Example 4106-Benzoyl-7-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[3860] In butanol (20 ml) was dissolved1-benzoyl-2-methyl-3-bromo-4-piperidone (240 mg), followed by theaddition of thioformamide (160 mg). The resulting mixture was stirred at100° C. for 2.5 hours. After the reaction mixture was cooled to roomtemperature, it was subjected to Celite filtration. The filtrate waswashed with a saturated aqueous solution of sodium bicarbonate andsaturated aqueous NaCl solution, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (ethylacetate:hexane=1:2), whereby the title compound (56 mg) was obtained asa yellow oil.

[3861]¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.6 Hz), 2.88-3.10 (2H, m), 3.41(1H, br s), 3.94 (1H, br s), 5.97 (1H, br s), 7.38-7.48 (5H, m), 8.70(1H, s).

[3862] MS (FAB) m/z: 259 (M+H)⁺.

Referential Example 4116-tert-Butoxycarbonyl-7-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[3863] Under ice cooling, sodium hydride (60% in oil, 270 mg) was addedto butanol (70 ml), followed by stirring for 30 minutes. A butanolsolution (5 ml) of6-benzoyl-7-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (240 mg)was added to the reaction mixture. The resulting mixture was heatedunder reflux for 4 days. After water (5 ml) was added to the reactionmixture and the mixture was heated under reflux for 30 minutes, thereaction mixture was cooled to room temperature. To the reaction mixturewas added di-tert-butyl dicarbonate (883 mg) and they were stirred atroom temperature for 8 hours. The reaction mixture was concentratedunder reduced pressure. To the residue were added 3N hydrochloric acid(10 ml) and ethyl acetate to separate the resulting mixture into layers.The organic layer thus collected was dried over anhydrous sodium sulfateand distilled to remove the solvent. The residue was purified bychromatography on a silica gel column (ethyl acetate:hexane=1:4),whereby the title compound (168 mg) was obtained as a yellow oil.

[3864]¹H-NMR (CDCl₃) δ: 1.46 (3H, d, J=5.6 Hz), 1.49 (9H, s), 2.85-2.92(2H, m), 3.10 (1H, m), 4.27-4.50 (1H, m), 5.23-5.52 (1H, m), 8.65 (1H,s).

[3865] MS (FAB) m/z: 255 (M+H)⁺.

Referential Example 412 Lithium6-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

[3866] In the same manner as in Referential Example 405, the titlecompound was obtained.

[3867]¹H-NMR (DMSO-d₆) δ: 1.38-1.40 (3H, m), 1.43 (9H, s), 2.60-2.82(2H, m), 3.11 (1H, br s), 4.15 (1H, br s), 5.10-5.32 (1H, m).

[3868] MS (FAB) m/z: 298 M⁺.

Referential Example 413 4-Ethoxycarbonylthiazole

[3869] Formamide (100 ml) was stirred under ice cooling, followed by theaddition of diphosphorus pentasulfide (27.48 g) in the form of a solid.The resulting mixture was stirred overnight at room temperature. Water(200 ml) was added and then the mixture was extracted with diethyl ether(8×200 ml). The organic layers were combined, washed with saturatedaqueous NaCl solution, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent, whereby thioformamide(35.8 g) was obtained as a yellow oil. While stirring, ethylbromopyruvate (20.0 g) was added to the resulting oil. After theaddition of ethanol (100 ml) to the reaction mixture, ethylbromopyruvate (45.04 g) was added further. The resulting mixture wasstirred at room temperature for 3 hours. The solvent was distilled offunder reduced pressure. Methylene chloride was added to the residue. Theresulting mixture was washed with a saturated aqueous solution of sodiumbicarbonate and saturated aqueous NaCl solution, dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent, whereby the title compound (42.73 g) was obtained as a brownoil.

[3870]¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.3 Hz), 4.45 (2H, q, J=7.3 Hz),8.26 (1H, d, J=2.0 Hz), 8.86 (1H, d, J=2.0 Hz).

[3871] MS (EI) m/z: 157 M⁺.

Referential Example 414 4-Formylthiazole

[3872] In anhydrous tetrahydrofuran (150 ml) was dissolved4-ethoxycarbonylthiazole (15.2 g) and the resulting solution was cooledto −78° C. Diisobutylaluminum hydride (a 0.95 mole hexane solution, 102ml) was added dropwise, followed by stirring for 1 hour at a temperaturemaintained at −78° C. After the addition of methanol (20 ml) and heatingto room temperature, the reaction mixture was subjected to Celitefiltration. The precipitate so obtained was washed with tetrahydrofuranand ethyl acetate and then added to a saturated aqueous solution ofammonium chloride. The resulting mixture was extracted with methylenechloride. The organic layers were combined and distilled under reducedpressure to remove the solvent. The residue was then dissolved inmethylene chloride. The resulting solution was washed with saturatedaqueous NaCl solution, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent, whereby the title compound(7.37 g) was obtained as a yellow solid.

[3873]¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J=2.0 Hz), 8.92 (1H, d, J=2.0 Hz),10.15 (1H, s)

[3874] MS (EI) m/z: 113 M⁺.

Referential Example 415 4-(2-Nitro-1-propenyl)thiazole

[3875] In isopropyl alcohol (100 ml) was dissolved 4-formylthiazole(10.9 g), followed by the addition of potassium fluoride (280 mg) andnitromethane (14.46 g). The resulting mixture was stirred at 60 to 65°C. for 2 hours. The reaction mixture was then stirred overnight at roomtemperature. The solvent was distilled off under reduced pressure. Theresidue was dissolved in benzene (50 ml), followed by the addition ofacetic anhydride (12.29 g) and 4-(dimethylamino)pyridine (588 g). Theresulting mixture was heated under reflux for 2 hours. The solvent wasdistilled off under reduced pressure. Methylene chloride was added tothe residue. The resulting mixture was washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was then dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=1:1), whereby the title compound (8.73 g)was obtained as vividly yellow crystals.

[3876]¹H-NMR (CDCl₃) δ: 2.78 (3H, d, J=0.5 Hz), 7.68 (1H, d, J=2.0 Hz),8.03 (1H, m), 8.92 (1H, d, J=2.0 Hz).

[3877] MS (EI) m/z: 170 M⁺.

Referential Example 4164-[2-[N-(tert-Butoxycarbonyl)amino]propyl]thiazole

[3878] Under ice cooling, lithium aluminum hydride (2.41 g) wassuspended in anhydrous tetrahydrofuran (50 ml). An anhydroustetrahydrofuran solution (90 ml) of 4-(2-nitro-1-propenyl)thiazole (10.8g) was added dropwise to the resulting suspension. After stirring at thesame temperature for 40 minutes, sodium sulfate 10 hydrate (15 g) wasadded and the resulting mixture was stirred for 45 minutes. The reactionmixture was subjected to Celite filtration. From the precipitate, anorganic substance was extracted with hot methanol. The organic layerswere combined and distilled under reduced pressure to remove thesolvent. Methylene chloride (50 ml), sodium carbonate (3.4 g) anddi-tert-butyl dicarbonate (13.86 g) were added to the residue, followedby stirring at room temperature for 2 hours. The reaction mixture waswashed with water, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (Φ 4×20 cm, hexane:ethylacetate=3:1→3:2), whereby the title compound (2.86 g) was obtained as abrown oil.

[3879]¹H-NMR (CDCl₃) δ: 1.13, 1.16 (total 3H, d each, J=6.6, 6.4 Hz),1.42 (9H, s), 2.91-3.09 (2H, m), 4.00-4.11 (1H, m), 5.03-5.08 (1H, m),7.05-7.10 (1H, m), 8.75-8.77 (1H, m).

[3880] MS (FAB) m/z: 243 (M+H)⁺.

Referential Example 4176-(tert-Butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[3881] In ethanol (26 ml) was dissolved4-[2-[N-(tert-butoxycarbonyl)amino]propyl]thiazole (1.07 g), followed bythe addition of paraformaldehyde (90%, 2.94 g) and a 1N solution (13 ml)of hydrochloride in ethanol. The resulting mixture was charged in asealed tube and stirred at 100° C. for 28 hours. During stirring,operation of cooling to room temperature, loosening the lid and therebyreducing the internal pressure of the tube was carried out severaltimes. The solvent was then distilled off under reduced pressure. To theresidue were added methylene chloride (18 ml), triethylamine (2.6 ml)and di-tert-butyl dicarbonate (1.45 g), followed by stirring at roomtemperature for 3 hours. The reaction mixture was washed with water,dried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by column chromatography(hexane:ethyl acetate=4:1) using, as a carrier, silica gel, whereby thetitle compound (625 mg) was obtained as a pale yellow solid.

[3882]¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=6.8 Hz), 1.49 (9H, s), 2.77 (1H,d, J=16.6 Hz), 3.09-3.14 (1H, m), 4.21 (1H, d, J=16.8 Hz), 4.84 (1H, brs), 5.06 (1H, br s), 8.69 (1H, s).

[3883] MS (FAB) m/z: 255 (M+H)⁺.

Referential Example 418 4-Formyl-2-(trans-β-styryl)oxazole

[3884] To a solution of 4-ethoxycarbonyl-2-(trans-β-styryl)oxazole (8.57g) (J. Org. Chem. 1996, 61, 6496-6497) in methylene chloride (80 ml) wasadded dropwise diisobutylaluminum hydride (a 1.0 mole hexane solution,66.0 ml) at −78° C. After stirring for 15 minutes, methanol (11 ml) wasadded dropwise and the resulting mixture was warmed up to roomtemperature over 1 hour. The reaction mixture was then subjected toCelite filtration. The pasty substance thus obtained was dissolved inethyl acetate (200 ml) and a saturated aqueous solution (200 ml) ofammonium chloride. The resulting solution was separated into layers. Thewater layer was extracted with methylene chloride (2×100 ml). Theorganic layers were combined and washed with a saturated aqueoussolution (100 ml) of sodium bicarbonate and saturated aqueous NaClsolution (100 ml), followed by the addition of the filtrate upon Celitefiltration. The resulting mixture was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column (methylenechloride:ethyl acetate=5:1→methylene chloride:methanol=10:1), wherebythe title compound (5.86 g) was obtained as colorless needle crystals.

[3885]¹H-NMR (CDCl₃) δ: 6.96 (1H, d, J=16.6 Hz), 7.35-7.45 (3H, m), 7.56(2H, d, J=6.4 Hz), 7.67 (1H, d, J=16.6 Hz), 8.26 (1H, s), 9.98 (1H, s).

[3886] MS (FAB) m/z: 200 (M+H)⁺.

Referential Example 419 2-(trans-β-Styryl)-4-vinyloxazole

[3887] To a solution of (methyl)triphenylphosphonium bromide (8.16 g,22.8 mmol) in tetrahydrofuran (80 ml) was added dropwise n-butyl lithium(a 1.54N hexane solution, 14.2 ml) at 0° C., followed by stirring atroom temperature for 30 minutes. The reaction mixture was cooled to 0°C. again and a solution of 4-formyl-2-(trans-β-styryl)oxazole (3.64 g)in tetrahydrofuran (20 ml) was added thereto. The resulting mixture washeated to room temperature. After stirring for 2 hours, water (200 ml)and ethyl acetate (100 ml) were added to separate the reaction mixtureinto layers. The water layer was extracted with ethyl acetate (50 ml).The organic layers were combined, washed with saturated aqueous NaClsolution (100 ml), dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (hexane:ethyl acetate=4:1→3:1),whereby the title compound (2.84 g) was obtained as a pale yellow oil.

[3888]¹H-NMR (CDCl₃) δ: 5.33 (1H, dd, J=10.7, 1.5 Hz), 5.98 (1H, dd,J=17.6, 1.5 Hz), 6.56 (1H, dd, J=17.6, 10.7 Hz), 6.95 (1H, d, J=16.6Hz), 7.31-7.42 (3H, m), 7.49-7.56 (4H, m).

[3889] MS (FAB) m/z: 198 (M+H)⁺.

Referential Example 420 4-(2-Hydroxyethyl)-2-(trans-β-styryl)oxazole

[3890] To a solution of 2-(trans-β-styryl)-4-vinyloxazole (13.0 g) intetrahydrofuran (500 ml) was added 9-borabicyclo[3.3.1]nonane (a 0.5mole tetrahydrofuran solution, 158 ml) at 0° C. The resulting mixturewas stirred at room temperature for 15 hours. At 0° C., water (10 ml), a3N aqueous solution of sodium hydroxide (80 ml) and aqueous hydrogenperoxide (80 ml) were successively added dropwise to the reactionmixture, followed by stirring at room temperature for 6 hours. Water(600 ml) and ethyl acetate (200 ml) were added to the reaction mixtureto separate the reaction mixture into layers. The water layer wasextracted with ethyl acetate (200 ml). The organic layers were combined,washed with saturated aqueous NaCl solution (200 ml), dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (hexane:ethyl acetate=2:1→only ethyl acetate), whereby the titlecompound (14.1 g) was obtained as a colorless solid.

[3891]¹H-NMR (CDCl₃) δ: 2.69 (1H, br s), 2.80 (2H, t, J=5.6 Hz),3.90-3.97 (2H, m), 6.91 (1H, d, J=16.6 Hz), 7.30-7.42 (4H, m), 7.43-7.56(3H, m).

[3892] MS (FAB) m/z: 216 (M+H)⁺.

Referential Example 421N-[2-[2-(trans-β-styryl)oxazol-4-yl]ethyl]phthalimide

[3893] To a solution of 4-(2-hydroxyethyl)-2-(trans-β-styryl)oxazole(292 mg) in tetrahydrofuran (15 ml) were added phthalimide (200 mg),triphenylphosphine (357 mg) and diethyl azodicarboxylate (214 μl) atroom temperature, followed by stirring for 4 hours. The reaction mixturewas distilled under reduced pressure to remove the solvent. The residuewas purified by chromatography on a silica gel column (hexane:ethylacetate=3:1), whereby the title compound (447 mg) was obtained as acolorless solid.

[3894]¹H-NMR (CDCl₃) δ: 2.98 (2H, t, J=7.2 Hz), 4.03 (2H, t, J=7.2 Hz),6.88 (1H, d, J=16.6 Hz), 7.28-7.45 (5H, m), 7.48 (2H, d, J=7.3 Hz), 7.71(2H, dd, J=5.4, 2.9 Hz), 7.84 (2H, dd, J=5.4, 2.9 Hz).

[3895] MS (FAB) m/z: 345 (M+H)⁺.

Referential Example 4224-[2-(tert-Butoxycarbonylamino)ethyl]-2-(trans-β-styryl)oxazole

[3896] To a solution ofN-[2-[2-(trans-β-styryl)oxazol-4-yl]ethyl]phthalimide (6.40 g) inethanol (150 ml) was added hydrazine monohydrate (1.50 ml) at roomtemperature. After stirring for 1 hour, hydrazine monohydrate (500 μl)was added again at room temperature, followed by stirring for 2 hours.At room temperature, methylene chloride (150 ml) and a saturated aqueoussolution (150 ml) of sodium bicarbonate and di-tert-butyl dicarbonate(13.4 g, 61.4 mmol) were added to the reaction mixture. After stirringfor 30 minutes, the reaction mixture was separated into layers. Thewater layer was extracted with methylene chloride (50 ml). The organiclayers were combined, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (hexane:ethyl acetate=2:1→1:1),whereby the title compound (5.06 g) was obtained as a colorless solid.

[3897]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.75 (2H, t, J=6.6 Hz), 3.46 (2H,dt, J=5.9, 6.6 Hz), 4.92 (1H, br s), 6.91 (1H, d, J=16.6 Hz), 7.29-7.45(4H, m), 7.48 (1H, d, J=16.6 Hz), 7.52 (2H, d, J=7.3 Hz)

[3898] MS (FAB) m/z: 315 (M+H)⁺.

Referential Example 4236-(tert-Butoxycarbonyl)-2-(trans-β-styryl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine

[3899] To a solution of4-[2-(tert-Butoxycarbonylamino)ethyl]-2-(trans-β-styryl)oxazole (190 mg)in toluene (15 ml) were added paraformaldehyde (54.5 mg) andp-toluenesulfonic acid (7.2 mg) at room temperature. After heating underreflux for 1 hour, the reaction mixture was allowed to cool down. Ethylacetate (15 ml) and a saturated aqueous solution (15 ml) of sodiumbicarbonate were added to the reaction mixture to separate it intolayers. The water layer was extracted with ethyl acetate(10 ml). Theorganic layers were combined, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (hexane:ethylacetate=3:1→2:1), whereby the title compound (153 mg) was obtained as acolorless transparent viscous substance.

[3900]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.67 (2H, br s), 3.73 (2H, br s),4.55 (2H, s), 6.90 (1H, d, J=16.1 Hz), 7.29-7.42 (3H, m), 7.46 (1H, d,J=16.1 Hz), 7.52 (2H, d, J=7.3 Hz).

[3901] MS (FAB) m/z: 327 (M+H)⁺.

Referential Example 4246-(tert-Butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine

[3902] To a solution of6-(tert-butoxycarbonyl)-2-(trans-β-styryl)-4,5,6,7-tetrahydrooxazol[5,4-c]pyridine(803 mg) in tetrahydrofuran (16 ml) were added acetone (8.0 ml), water(4.0 ml), N-methylmorpholine oxide (577 mg) and osmium tetraoxide (a0.039 mole aqueous solution, 3.20 ml) at room temperature, followed bystirring overnight. Ethyl acetate (50 ml) and a 10% aqueous solution (50ml) of sodium thiosulfate were added to the reaction mixture to separateit into layers. The water layer was extracted with ethyl acetate (30ml). The organic layers were combined, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Asolution of the resulting residue in tetrahydrofuran (16 ml) were addedmethanol (8.0 ml), water (8.0 ml) and sodium metaperiodate (790 mg) atroom temperature. After stirring for 3 hours, ethyl acetate (30 ml) andwater (50 ml) were added to the reaction mixture to separate it intolayers. The water layer was extracted with ethyl acetate (20 ml). Theorganic layers were combined, washed with a saturated aqueous solutionof sodium bicarbonate (50 ml), dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (hexane:ethylacetate=4:1→2:1), whereby the title compound (234 mg) was obtained as acolorless transparent glassy substance.

[3903]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.77 (2H, br s), 3.77 (2H, br s),4.62 (2H, s), 9.70 (1H, s).

[3904] The resulting aldehyde was unstable so that it was provided forthe subsequent reaction immediately.

Referential Example 4256-(tert-Butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazol[5,4-c]pyridine

[3905] To a solution of6-(tert-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazol[5,4-c]pyridine(225 mg) in methanol (9.0 ml) were added sodium cyanide (220 mg) andmanganese dioxide (780 mg) at room temperature, followed by stirring for30 minutes. The reaction mixture was subjected to Celite filtration byusing ethyl acetate. The filtrate was washed with water (50 ml) andsaturated saline (50 ml), dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (hexane:ethylacetate=3:2→1:1), whereby the title compound (120 mg) was obtained as acolorless transparent glassy substance.

[3906]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.73 (2H, br s), 3.74 (2H, br s),4.01 (3H, s), 4.59 (2H, s).

[3907] MS (FAB) m/z: 283 (M+H)⁺.

Referential Example 426 Lithium6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazol[5,4-c]pyridine-2-carboxylate

[3908] To a solution of6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine(311 mg) in tetrahydrofuran (8.0 ml) were added water (2.0 ml) andlithium hydroxide (25.0 mg) at room temperature. After stirring for 10minutes, the reaction mixture was distilled under reduced pressure toremove the solvent, whereby the title compound (280 mg) was obtained asa colorless solid. The residue was provided for the subsequent reactionwithout purification.

[3909]¹H-NMR (DMSO-d₆) δ: 1.42 (9H, s), 3.31 (2H, s), 3.60 (2H, d, J=5.4Hz), 4.42 (2H, s).

Referential Example 4272-Methoxycarbonyl-6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine

[3910] To a solution of6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine(500 mg) in methylene chloride (15 ml) was added trifluoroacetic acid(15 ml) at room temperature, followed by stirring for 10 minutes. Thereaction mixture was concentrated under reduced pressure. To theresulting residue were added methylene chloride (20 ml), triethylamine(495 μl), acetic acid (205 μl), formalin (230 μl) and sodiumtriacetoxyborohydride (570 mg) at room temperature. After stirring for15 minutes, methylene chloride (20 ml) and a saturated aqueous solution(50 ml) of sodium bicarbonate were added to the reaction mixture toseparate it into layers. The water layer was extracted with methylenechloride (3×20 ml). The organic layers were combined, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (chloroform:methanol=20:1→10:1), whereby the title compound (257mg) was obtained as a colorless transparent oil.

[3911]¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.72-2.78 (2H, m), 2.78-2.83 (2H,m), 3.61 (2H, t, J=1.7 Hz), 4.00 (3H, s).

[3912] MS (FAB) m/z: 197 (M+H)⁺.

Referential Example 4281-(tert-Butoxycarbonyl)-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[3913] To a solution of2-methoxycarbonyl-6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (250mg) in tetrahydrofuran (8.0 ml) were added water (2.0 ml) and lithiumhydroxide (30.0 mg) at room temperature. After stirring for 10 minutesthe solvent was distilled off under reduced pressure. To a solution ofthe resulting residue in N,N-dimethylformamide (4.0 ml) were added1-(tert-butoxycarbonyl)piperazine (260 mg), 1-hydroxybenzotriazolemonohydrate (189 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (268 mg) at room temperature. After stirring for 63 hours,methylene chloride (20 ml) and a saturated aqueous solution (30 ml) ofsodium bicarbonate were added to the reaction mixture to separate itinto layers. The water layer was extracted with methylene chloride (2×10ml). The organic layers were combined and washed with water (150 ml).The resulting water layer was extracted with methylene chloride (3×10ml). The organic layers were combined, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column (methylenechloride:acetone=1:1→1:3), whereby the title compound (359 mg) wasobtained as a colorless transparent viscous substance.

[3914]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.51 (3H, s), 2.71 (2H, t, J=4.5Hz), 2.79 (2H, t, J=4.5 Hz), 3.51 (4H, t, J=5.0 Hz), 3.60 (2H, s), 3.75(2H, t, J=5.0 Hz), 4.22 (2H, t, J=5.0 Hz).

[3915] MS (FAB) m/z: 351 (M+H)⁺.

Referential Example 4296-(tert-Butoxycarbonyl)-2-methylthio-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[3916] To a solution of 1-(tert-butoxycarbonyl)-4-piperidone (9.30 g) intetrahydrofuran (40 ml) was added N,N-dimethylformamide dimethylacetal(18.6 ml) at room temperature, followed by heating under reflux for 3days. After the reaction mixture was allowed to cool down to roomtemperature, it was concentrated under reduced pressure.

[3917] To a solution of the resulting residue in ethanol (120 ml) wereadded methylisothiourea sulfate (19.5 g) and sodium ethoxide (13.2 g) atroom temperature, followed by heating under reflux for 5 hours. Afterthe reaction mixture was allowed to cool down, water (700 ml) and ethylacetate (200 ml) were added to the reaction mixture to separate it intolayers. The water layer was then extracted with ethyl acetate (200 ml).The organic layers were combined, washed with saturated saline (200 ml),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (methylene chloride:acetone=20:1→15:1), whereby the titlecompound (1.82 g) was obtained as a colorless transparent viscoussubstance.

[3918]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.56 (3H, s), 2.89 (2H, t, J=5.9Hz), 3.72 (2H, t, J=5.9 Hz), 4.52 (2H, s), 8.27 (1H, s).

[3919] MS (FAB) m/z: 282 (M+H)⁺.

Referential Example 4306-(tert-Butoxycarbonyl)-2-methylsulfonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[3920] To a solution of6-(tert-butoxycarbonyl)-2-methylthio-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(2.20 g) in methylene chloride (80 ml) was added metachloroperbenzoicacid (3.37 g). After stirring for 4 hours, a 10% aqueous solution (100ml) of sodium thiosulfate and a saturated aqueous solution (100 ml) ofsodium bicarbonate were added to the reaction mixture and the mixturewas separated into layers. The water layer was extracted with methylenechloride (2×50 ml). The organic layers were combined, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (methylene chloride:acetone=20:1→10:1), whereby the titlecompound (2.34 g) was obtained as a colorless solid.

[3921]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.10 (2H, t, J=5.9 Hz), 3.34 (3H,s), 3.80 (2H, t, J=5.9 Hz), 4.71 (2H, s), 8.63 (1H, s).

[3922] MS (FAB) m/z: 314 (M+H)⁺.

Referential Example 4316-(tert-Butoxycarbonyl)-2-cyano-5,6,7,8-tetrahydrocyano[4,3-d]pyrimidine

[3923] To a solution of6-(tert-butoxycarbonyl)-2-methylsulfonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(330 mg) in methylene chloride (10 ml) was added tetrabutylammoniumcyanide (425 mg) at room temperature. After stirring at room temperaturefor 3 hours, the solvent was distilled off under reduced pressure. Theresidue was purified by chromatography on a silica gel column (methylenechloride:acetone=20:1), whereby the title compound (261 mg) was obtainedas pale yellow foam.

[3924]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.02 (2H, t, J=5.9 Hz), 3.78 (2H,t, J=5.9 Hz), 4.68 (2H, s), 8.55 (1H, s).

[3925] MS (FAB) m/z: 261 (M+H)⁺.

Referential Example 4326-(tert-Butoxycarbonyl)-2-methoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[3926] To a solution of6-(tert-butoxycarbonyl)-2-cyano-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(814 mg) in methanol (10 ml) was added concentrated sulfuric acid (5.0ml) at room temperature. The resulting mixture was stirred at 100° C.for 1 hour. After the reaction mixture was allowed to cool down, it wasconcentrated under reduced pressure. The residue was dissolved inmethylene chloride (15 ml), followed by the addition of triethylamine(2.20 ml) and di-tert-butyl dicarbonate (1.03 g) at room temperature.The resulting mixture was stirred at room temperature for 1 hour. Thereaction mixture was then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (methylenechloride:acetone=6:1→3:1), whereby the title compound (619 mg) wasobtained as a pale yellow viscous substance.

[3927]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.10 (2H, t, J=5.8 Hz), 3.79 (2H,t, J=5.8 Hz), 4.06 (3H, s), 4.71 (2H, s), 8.65 (1H, s).

[3928] MS (FAB) m/z: 294 (M+H)⁺.

Referential Example 433 Lithium6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate

[3929] In the same manner as in Referential Example 371, the titlecompound was obtained.

[3930]¹H-NMR (DMSO-d₆) δ: 2.30-2.60 (4H, m), 2.35 (3H, s), 3.34 (2H, s),6.50 (1H, s).

Referential Example 4341-(tert-Butoxycarbonyl)-4-[(6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)carbonyl]piperazine

[3931] In the same manner as in Example B-62, the title compound wasobtained.

[3932]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.49 (3H, s), 2.55-2.65 (2H, m),2.65-2.75 (2H, m), 3.45-3.55 (6H, m), 3.76 (4H, br s), 6.86 (1H, s).

[3933] MS (FAB) m/z: 350 (M+H)⁺.

Referential Example 435 Methyl2-tert-butoxycarbonylisoindoline-5-carboxylate

[3934] In the same manner as in Referential Example 363, the titlecompound was obtained.

[3935]¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 3.92 (3H, s), 4.65-4.72 (2H, m),4.73 (2H, s), 7.29 (0.5H, d, J=7.8 Hz), 7.34 (0.5H, d, J=7.8 Hz), 7.91(0.5H, s), 7.96 (1H, s), 7.98 (0.5H, s).

[3936] MS (FAB) m/z: 278 (M+H)⁺.

[3937] Elementary analysis for C₁₅H₁₉NO₄

[3938] Calculated: C, 64.97; H, 6.91; N, 5.05.

[3939] Found: C, 64.94; H, 7.13; N, 4.96.

[3940] In the same manner as in Referential Example 368, compounds shownin Referential Examples 436 and 437 were obtained.

Referential Example 436 2-tert-Butoxycarbonylisoindoline-5-carboxylicAcid

[3941]¹H-NMR (CDCl₃) δ: 1.53 (9H, s), 4.70-4.72 (2H, m), 4.75 (2H, s),7.32 (0.5H, d, J=7.3 Hz), 7.38 (0.5H, d, J=7.3 Hz), 7.97 (0.5H, s), 8.02(1H, s), 8.04 (0.5H, s).

[3942] MS (FAB) m/z: 264 (M+H)⁺.

[3943] Elementary analysis for C₁₄H₁₇NO₄

[3944] Calculated: C, 63.87; H, 6.51; N, 5.32.

[3945] Found: C, 63.79; H, 6.65; N, 5.12.

Referential Example 4374-tert-Butoxycarbonyl-3-carboxymethyl-1-[(5-chloroindol-2-yl)sulfonyl]piperazine

[3946]¹H-NMR (DMSO-d₆) δ: 1.33 (9H, s), 2.12-2.25 (1H, m), 2.30-2.42(2H, m), 2.35-3.57 (1H, m), 2.60-2.71 (1H, m), 2.90-3.02 (1H, m),3.54-3.65 (1H, m), 3.72-3.86 (2H, m), 4.43 (1H, br s), 6.99 (1H, s),7.30 (1H, dd, J=8.8, 1.8 Hz), 7.48 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=1.8Hz).

[3947] MS (FAB) m/z: 480 (M+Na)⁺.

Referential Example 4384-tert-Butoxycarbonyl-1-[(5-chloroindol-2-yl)sulfonyl]-3-[N-(2-hydroxyethyl)carbamoylmethyl]piperazine

[3948] In the same manner as in Referential Example 5, the titlecompound was obtained.

[3949]¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 2.30-2.90 (3H, m), 3.03-4.15 (7H,m), 4.62-4.71 (1H, m), 6.56 (1H, br s), 6.95 (1H, s), 7.28 (1H, dd,J=8.8, 1.7 Hz), 7.37 (1H, d, J=8.8 Hz), 7.64 (1H, d, J=1.7 Hz),10.01-10.70 (1H, br m).

[3950] FAB-MS m/z: 502 [(M+H)⁺, Cl³⁵], 504 [(M+H)⁺, Cl³⁷].

Referential Example 4394-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine

[3951] In tetrahydrofuran—methanol (10/1, 55 mL) was dissolved4-(tert-butoxycarbonyl)-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[(methoxycarbonyl)methyl]piperazine(2.5 g), followed by the addition of lithium borohydride (135 mg). Theresulting mixture was stirred for 48 hours. The solvent was distilledoff under reduced pressure. Water and chloroform were then added to thereaction mixture and the mixture was separated into layers. The organiclayer was dried over anhydrous magnesium sulfate and distilled underreduced pressure to remove the solvent. The residue was subjected tochromatography on a silica gel column (ethyl acetate:hexane=2:3),whereby the title compound (1.84 g) was obtained as a colorless oil.

[3952]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.60 (2H, m), 2.98-4.42 (9H, m),7.42-7.59 (6H, m), 8.01 (1H, d, J=1.2 Hz), 8.03 (1H, d, J=1.2 Hz), 8.21(1H, d, J=9.3 Hz).

[3953] MS (FAB) m/z: 584 [(M+H)⁺].

Referential Example 4404-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)2-(formylmethyl)piperazine

[3954] In the same manner as in Referential Example 285, the titlecompound was obtained.

[3955]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.64 (1H, dd, J=5.4, 17.4 Hz),2.95-3.15 (5H, m), 3.72 (1H, d, J=13.2 Hz), 3.94 (1H, m), 4.73 (1H, m),7.40-7.58 (6H, m), 8.00 (1H, d, J=1.2 Hz), 8.02 (1H, d, J=1.2 Hz), 8.20(1H, d, J=9.0 Hz), 9.62 (1H, s).

Referential Example 4414-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-[2-(1,4-dioxa-8-azaspiro[4,5]-decan-8-yl)ethyl]piperazine

[3956] In the same manner as in Referential Example 265, the titlecompound was obtained.

[3957]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.68 (4H, t, J=6.4 Hz), 1.83-3.20(12H, m), 3.61 (1H, m), 3.94 (4H, s), 4.0-4.25 (2H, m), 7.39-7.58 (6H,m), 8.01 (1H, d, J=1.5 Hz), 8.04 (1H, d, J=1.0 Hz), 8.22 (1H, d, J=9.3Hz).

[3958] MS (FAB) m/z: 709 [(M+H)⁺].

Referential Example 4424-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-[(1,3-dioxolan-2-ylmethyl]piperazine

[3959] In toluene (10 mL) were dissolved4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-(formylmethyl)piperazine(440 mg) and ethylene glycol (71 mg, followed by the addition ofp-TsOH.H₂O (15 mg). The resulting mixture was heated to 60° C. andstirred for 16 hours. Ethyl acetate was added to the reaction mixture.The resulting mixture was washed with a saturated aqueous solution ofsodium bicarbonate. The organic layer was dried over anhydrous MgSO₄ anddistilled under reduced pressure to remove the solvent, whereby thetitle compound (460 mg) was obtained as colorless amorphous.

[3960]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.63 (2H, m), 1.98 (2H, m),2.49-3.95 (3H, m), 3.66-4.13 (8H, m), 4.78 (1H, t, J=4.9 Hz), 7.17 (1H,m), 7.42-7.58 (5H, m), 8.02 (1H, d, J=1.5 Hz), 8.04 (1H, d, J=1.0 Hz),8.23 (1H, d, J=9.3 Hz).

[3961] MS (FAB) m/z: 626 [(M+H)⁺].

Referential Example 4431,4-Dibenzyl-2-[(1,3-dioxoisoindol-2-yl)methyl]piperazine

[3962] To a solution of 1,4-dibenzyl-2-(hydroxymethyl)piperazine (1.51g), phthalimide (0.790 g) and triphenylphosphine (1.40 g) intetrahydrofuran (20 ml) was added a 40% toluene solution (2.34 ml) ofdiethyl azodicarboxylate under ice cooling. The resulting mixture wasstirred at room temperature for 6 hours. Furthermore,1,4-dibenzyl-2-(hydroxymethyl)piperazine (0.87 g), phthalimide (0.486g), triphenylphosphine (0.81 g) and tetrahydrofuran (5 ml) were added tothe reaction mixture, followed by the addition of a 40% toluene solution(1.34 ml) of diethyl azodicarboxylate under ice cooling. The resultingmixture was stirred at room temperature for 18.5 hours. Phthalimide(0.405 g) and a 40% toluene solution (1.10 ml) of diethylazodicarboxylate were added under ice cooling, followed by stirring atroom temperature for 20 hours. The solvent was distilled off underreduced pressure. The residue was subjected to column chromatographytwice (3% methanol—methylene chloride for the first time and ethylacetate/hexane=1/3 for the second time) using as a carrier silica gel,whereby a crude product was obtained. The crude product was crystallizedfrom hexane—methylene chloride, collected by filtration and washed withhexane, whereby the title compound (0.243 g) was obtained as colorlesspowder.

[3963]¹H-NMR (CDCl₃) δ: 2.30-2.40 (4H, m), 2.50-2.60 (1H, m), 2.95-3.10(2H, m), 3.40-3.55 (2H, m), 3.60-3.65 (1H, m), 3.75-3.80 (1H, m),3.95-4.05 (1H, m), 4.15-4.25 (1H, m), 7.10-7.35 (10H, m), 7.70-7.75 (2H,m), 7.80-7.85 (2H, m).

[3964] MS (FAB) m/z: 426 (M+H)⁺.

Referential Example 4441-[(5-Chloro-1-phenylsulfonyl)piperazin-2-yl]-3-[(1,4-dioxoisoindol-2-yl)methyl]piperazine

[3965] In the same manner as in Referential Example 266, the titlecompound was obtained.

[3966]¹H-NMR (CDCl₃) δ: 2.77-2.88 (2H, m), 2.98-3.09 (2H, m), 3.16-3.18(1H, m), 3.69-3.72 (3H, m), 3.81 (1H, broad d, J=12.6 Hz), 7.36 (1H, s),7.40-7.46 (3H, m), 7.52-7.56 (2H, m), 7.71-7.74 (2H, m), 7.83-7.86 (2H,m), 7.99 (2H, dd, J=1.1, 7.4 Hz), 8.22 (1H, d, J=9.2 Hz).

[3967] MS (FAB) m/z: 599 [(M+H)⁺, Cl³⁵], 601 [(M+H)⁺, Cl³⁷].

Referential Example 4451,4-Di(tert-butoxycarbonyl)-2-(2-phenoxyethyl)piperazine

[3968] To a solution of1,4-di(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (0.660 g, 2mmol) and triphenylphosphine (0.577 g, 2.2 mmol) in tetrahydrofuran (10ml) were added a solution of phenol (0.188 g, 2 mmol) in tetrahydrofuran(5 ml) and diethyl azodicarboxylate (0.35 ml, 2.2 mmol), followed bystirring at room temperature for 4 hours. The reaction mixture waspurified by flash column chromatography (ethyl acetate/n-hexane=1/4)using as a carrier silica gel, whereby the title compound (0.611 g, 75%)was obtained as a colorless solid.

[3969]¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 1.46 (9H, s), 1.91-1.96 (1H, m),2.06-2.12 (1H, m), 2.81-3.00 (2H, broad), 3.94-3.98 (6H, m), 4.40 (1H,broad), 6.86 (2H, d, J=7.8 Hz), 6.92 (1H, dd, J=7.2, 7.2 Hz), 7.23-7.27(2H, m).

[3970] MS (FAB) m/z: 407 (M+H)⁺.

Referential Example 4461-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(2-phenoxyethyl)piperazine

[3971] In the same manner as in Referential Example 220, the titlecompound was obtained.

[3972]¹H-NMR (CDCl₃) δ: 1.81-1.86 (2H, m), 2.70-2.76 (1H, m), 2.93-3.07(4H, m), 3.76-3.85 (2H, m), 4.05 (2H, t, J=5.8 Hz), 6.84 (2H, d, J=7.8Hz), 6.92-6.96 (1H, m), 7.36 (1H, s), 7.40-7.45 (4H, m), 7.50-7.56 (3H,m), 8.00 (2H, d, J=7.5 Hz), 8.22 (1H, d, J=9.2 Hz).

[3973] MS (FAB) m/z: 560 [(M+H)⁺, Cl³⁵], 562 [(M+H)⁺, Cl³⁷].

Referential Example 447 1,4-Di(tert-butoxycarbonyl)-2-[2-(2-naphthoxy)ethyl]piperazine

[3974] In the same manner as in Referential Example 445, the titlecompound was obtained.

[3975]¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 1.47 (9H, s), 1.99-2.04 (1H, m),2.16 (1H, m), 2.82-3.02 (2H, broad), 4.00-4.12 (6H, broad m), 4.46 (1H,broad), 7.09-7.12 (2H, m), 7.29-7.33 (1H, m), 7.39-7.43 (1H, m),7.67-7.75 (3H, m).

[3976] MS (FAB) m/z: 457 (M+H)⁺.

Referential Example 4481-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[2-(2-naphthoxy)ethyl)piperazine

[3977] In the same manner as in Referential Example 220, the titlecompound was obtained.

[3978]¹H-NMR (CDCl₃) δ: 1.89-1.95 (2H, m), 2.73-2.79 (1H, m), 2.92-3.09(4H, m), 3.79 (1H, broad d, J=10.9 Hz), 3.87 (1H, broad d, J=12.2 Hz),4.18 (2H, t, J=6.0 Hz), 7.06-7.10 (2H, m), 7.31-7.35 (1H, m), 7.36 (1H,s), 7.39-7.48 (5H, m), 7.52-7.56 (1H, m), 7.69-7.72 (2H, m), 7.76 (1H,d, J=8.3 Hz), 8.00 (2H, d, J=7.8 Hz), 8.22 (1H, d, J=9.2 Hz).

[3979] MS (FAB) m/z: 610 [(M+H)⁺, Cl³⁵], 612 [(M+H)⁺, Cl³⁷].

Referential Example 4491-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[2-(tert-butyldiphenylsilyloxy)ethyl]piperazine

[3980] In the same manner as in Referential Example 266, the titlecompound was obtained.

[3981]¹H-NMR (CDCl₃) δ: 1.01 (9H, s), 1.55-1.61 (2H, m), 2.63-2.68 (1H,m), 2.88-3.01 (4H, m), 3.73-3.80 (4H, m), 7.33-7.45 (10H, m), 7.49-7.56(2H, m), 7.61-7.64 (4H, m), 8.01 (2H, dd, J=1.1, 8.4 Hz), 8.22 (1H, d,J=9.3 Hz).

[3982] MS (FAB) m/z: 722 (M+H)⁺.

Referential Example 4501-(tert-Butoxycarbonyl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]-4-[(1-phenylsulfonyl-5-chloroindol-2-yl)sulfonyl]piperazine

[3983] In the same manner as in Example 363, the title compound wasobtained.

[3984]¹H-NMR (CDCl₃) δ: 1.00 (9H, s), 1.38 (9H, s), 1.84-1.92 (2H, m),2.86-2.93 (1H, m), 3.02-3.14 (2H, m), 3.32 (1H, broad), 3.58-3.62 (2H,m), 3.92 (2H, broad d, J=12.4 Hz), 4.42 (1H, broad), 7.29 (1H, s),7.32-7.43 (10H, m), 7.51-7.58 (5H, m), 7.99-8.01 (2H, m), 8.17 (1H, d,J=9.0 Hz).

[3985] MS (FAB) m/z: 822 (M+H)⁺.

Referential Example 4511-(tert-Butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-(2-hydroxyethyl)piperazine

[3986] To a solution of4-[(1-benzenesulfonyl-5-chloroindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]piperazine(4.48 g) in tetrahydrofuran (20 ml) was added a 11.0M tetrahydrofuransolution (5.5 ml) of tetrabutylammonium fluoride, followed by stirringat room temperature for 3.5 hours. After concentration under reducedpressure, the residue was purified by flash column chromatography (ethylacetate:hexane=1:9 to 1:0) using as a carrier silica gel, whereby thetitle compound (0.75 g) was obtained as a colorless solid.

[3987]¹H-NMR (DMSO-d₆) δ: 1.33 (9H, s), 1.74-1.77 (2H, m), 2.24-2.40(2H, m), 3.04 (1H, m), 3.35-3.46 (2H, m), 3.56-3.63 (2H, m), 3.85-3.88(1H, broad d, J=13.2 Hz), 4.25 (1H, broad), 4.43 (1H, broad), 6.98 (1H,d, J=0.7 Hz), 7.29 (1H, dd, J=1.9, 8.8 Hz), 7.46-7.48 (1H, m), 7.74 (1H,m).

[3988] MS (FAB) m/z: 444 (M+H)⁺.

Referential Example 4521,4-Bis(tert-butoxycarbonyl)-2-(2-tosyloxyethyl)piperazine

[3989] A solution of1,4-di(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (5.05 g) andp-toluenesulfonyl chloride (4.34 g) in methylene chloride (200 ml) wascooled to 0° C., followed by the dropwise addition of triethylamine (11ml). The resulting mixture was stirred at 0° C. for 1 hour and at roomtemperature for 1 day. The reaction mixture was concentrated underreduced pressure. After dilution with ethyl acetate, the residue waswashed with 1N hydrochloric acid, water and saturated aqueous NaClsolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by flash columnchromatography (ethyl acetate/hexane=1/4 to 1/1) using, as a carrier,silica gel, whereby the title compound (4.82 g) was obtained as acolorless solid.

[3990]¹H-NMR (CDCl₃) δ: 1.44 (18H, s), 1.78-1.84 (1H, m), 1.94 (1H,broad), 2.44 (3H, s), 2.86 (3H, broad), 3.85 (2H, broad), 3.97-4.07 (3H,m), 4.21 (1H, broad), 7.33 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.3 Hz).

[3991] MS (FAB) m/z: 485 (M+H)⁺.

Referential Example 4531,4-Bis(tert-butoxycarbonyl)-2-[2-(2-oxo-1,3-oxazolan-3-yl)ethyl]piperazine

[3992] To a suspension of sodium hydride (60%, 57 mg) inN,N-dimethylformamide (20 ml), 2-oxazolidone (0.122 g) was added,followed by stirring at 90° C. for 1 hour. A solution of1,4-di(tert-butoxycarbonyl)-2-(2-tosyloxyethyl)piperazine (0.686 g) inN,N-dimethylformamide (15 ml) was added to the reaction mixture. Theresulting mixture was stirred at 90° C. for 4 hours. The reactionmixture was concentrated under reduced pressure. The residue was dilutedwith ethyl acetate, washed with water and saturated aqueous NaClsolution, dried over magnesium sulfate and concentrated under reducedpressure, whereby the title compound (0.515 g) was obtained as acolorless solid.

[3993]¹H-NMR (CDCl₃) δ: 1.46 (8H, s), 1.47 (10H, s), 1.78-1.85 (2H, m),2.81-2.95 (3H, m), 3.39-3.64 (2H, m), 3.85-4.05 (2H, broad), 4.00 (2H,broad d, J=13.4 Hz), 4.09-4.28 (2H, m), 4.30-4.34 (2H, m).

[3994] MS (FAB) m/z: 400 (M+H)⁺.

Referential Example 4541-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[2-(2-oxo-1,3-oxazolan-3-yl)ethyl]piperazine

[3995] In the same manner as in Referential Example 220, the titlecompound was obtained.

[3996]¹H-NMR (CDCl₃) δ: 1.51-1.76 (2H, m), 2.69-2.74 (1H, m), 2.77-2.85(2H, m), 2.96-3.03 (2H, m), 3.20-3.27 (1H, m), 3.48-3.55 (2H, m),3.59-3.69 (2H, m), 3.83 (1H, broad d, J=11.7 Hz), 4.30-4.40 (2H, m),7.39-7.46 (4H, m), 7.51-7.57 (2H, m), 7.99-8.02 (2H, m), 8.22 (1H, d,J=9.0 Hz).

[3997] MS (FAB) m/z: 553 [(M+H)⁺, Cl³⁵], 555 [(M+H)⁺, Cl³⁷].

Referential Example 455 4,5-Bis(bromomethyl)thiazole

[3998] At room temperature, 4,5-dimethylthiazole (5.00 g),N-bromosuccinic imide (15.7 g) and α,α′-azobisisobutyronitrile (362 mg)were dissolved in ethylene dichloride (500 ml), followed by heatingunder reflux for 1 hour. After completion of the reaction, the solventwas distilled off and the residue was purified by chromatography on asilica gel column (hexane:diethyl ether=1:4), whereby the title compound(5.24 g, 44%) was obtained.

[3999]¹H-NMR (CDCl₃) δ: 4.64 (2H, s), 4.74 (2H, s), 8.75 (1H, s).

Referential Example 4565,6-Dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine

[4000] Under ice cooling, 4,5-bis(bromomethyl)thiazole (600 mg) and1,2-dimethylhydrazine dihydrochloride (294 mg) were suspended in ethanol(20 ml). Triethylamine (1.23 ml) was added in one portion to thereaction mixture, followed by stirring at room temperature for 30minutes and then, at 50° C. for 30 minutes. The solvent was distilledoff and the residue was purified by chromatography on a silica gelcolumn (5% methanol—methylene chloride), whereby the title compound (90mg, 24%) was obtained.

[4001]¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 2.56 (3H, s), 3.92 (2H, s), 4.06(2H, br s), 8.68 (1H, s).

[4002] MS (FAB) m/z: 170 (M+H)⁺.

Referential Example 4573-(Methoxycarbonylmethyl)-1-[[1-phenylsulfonyl-5-(trimethylsilylethynyl)indol-2-yl]sulfonyl]piperazine

[4003] In the same manner as in Referential Example 226, the titlecompound was obtained.

[4004]¹H-NMR (CDCl₃) δ: 0.25 (9H, s), 2.38 (1H, dd, J=16.2, 8.8 Hz),2.46 (1H, dd, J=16.2, 4.2 Hz), 2.76 (1H, dd, J=12.5, 10.0 Hz), 2.91-2.99(1H, m), 2.99-3.07 (2H, m), 3.17-3.25 (1H, m), 3.67 (3H, s), 3.69-3.78(2H, m), 7.38-7.44 (3H, m), 7.54 (1H, t, J=7.6 Hz), 7.58 (1H, dd, J=8.9,1.6 Hz), 7.68 (1H, d, J=1.6 Hz), 7.98-8.02 (2H, m), 8.22 (1H, d, J=8.9Hz).

[4005] MS (FAB) m/z: 574 (M+H)⁺.

Referential Example 4581,4-Bis(t-butoxycarbonyl)-2-[2-[(morpholin-4-yl)sulfonyl]ethyl]piperazine

[4006] In the same manner as in Referential Example 293, the titlecompound was obtained.

[4007]¹H-NMR (CDCl₃) δ: 1.47 (18H, s), 1.95-2.00 (1H, m), 2.10-2.20 (1H,m), 2.70-3.10 (5H, m), 3.25 (4H, t, J=4.7 Hz), 3.75 (4H, t, J=4.7 Hz),3.80-4.30 (4H, m).

[4008] MS (FAB) m/z: 464 (M+H)⁺.

Referential Example 4591-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[2-[(morpholin-4-yl)sulfonyl]ethyl]piperazine

[4009] In the same manner as in Referential Example 220, the titlecompound was obtained.

[4010]¹H-NMR (CDCl₃) δ: 1.80-1.90 (1H, m), 1.90-2.00 (1H, m), 2.60-2.70(1H, m), 2.80-3.10 (6H, m), 3.20-3.30 (4H, m), 3.60-3.85 (6H, m),7.40-7.50 (4H, m), 7.50-7.60 (2H, m), 8.00-8.10 (2H, m), 8.22 (1H, d,J=9.1 Hz).

[4011] MS (FAB) m/z: 617 [(M+H)⁺, Cl³⁵], 619 [(M+H)⁺, Cl³⁷].

Referential Example 4601,4-Bis(tert-butoxycarbonyl)-2-hydroxymethylpiperazine

[4012] In the same manner as in Referential Example 284, the titlecompound was obtained.

[4013]¹H-NMR (CDCl₃) δ: 1.46-1.47 (18H, m), 2.70-4.400 (10H).

Referential Example 461 1,4-Bis(tert-butoxycarbonyl)-2-formylpiperazine

[4014] In the same manner as in Referential Example 285, the titlecompound was obtained.

[4015]¹H-NMR (CDCl₃) δ: 1.45-1.50 (18H, m), 2.80-3.00 (1H, m), 3.00-3.20(2H, m), 3.70-4.00 (2H, m), 4.40-4.70 (2H, m), 9.59 (1H, s).

[4016] MS (FAB) m/z: 315 (M+H)⁺.

Referential Example 4621,4-Bis(tert-butoxycarbonyl)-2-(2-ethoxycarbonylethenyl)piperazine

[4017] In a 50-ml two-necked flask, sodium hydride (141 mg, 60% in oil)was charged, followed by purging with argon. Tetrahydrofuran (5 ml) wasadded and then, triethyl phosphonoacetate (700 μl) was added under icecooling. The resulting mixture was stirred at room temperature for 15minutes. The reaction mixture was cooled again and under ice cooling, asolution of 1,4-bis(tert-butoxycarbonyl)-2-formylpiperazine (911 mg)dissolved in tetrahydrofuran (7 ml) was added dropwise, followed bystirring at room temperature for 4 hours. After completion of thereaction, water was added and then ethyl acetate was added, whereby themixture was separated into layers. The organic layer thus obtained waswashed with saturated aqueous NaCl solution, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was subjected to flash column chromatography (hexane:ethylacetate=2:1) using, as a carrier, silica gel, whereby the title compound(920 mg, 83%) was obtained as a pale yellow oil.

[4018]¹H-NMR (CDCl₃) δ: 1.20-1.30 (3H, m), 1.40-1.50 (18H, m), 2.75-3.20(3H, m), 3.80-4.80 (6H, m), 5.93 (1H, dd, J=15.9, 2.0 Hz), 6.82 (1H, dd,J=15.9, 4.4 Hz).

[4019] MS (FAB) m/z: 385 (M+H)⁺.

Referential Example 4631,4-Bis(tert-butoxycarbonyl)-2-(2-ethoxycarbonylethyl)piperazine

[4020] In the same manner as in Referential Example 287, the titlecompound was obtained.

[4021]¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.46 (9H,s), 1.70-1.85 (1H, m), 1.85-2.00 (1H, m), 2.20-2.40 (2H, m), 2.70-3.00(3H, m), 3.80-4.20 (6H, m).

[4022] MS (FAB) m/z: 387 (M+H)⁺.

Referential Example 4641-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(2-ethoxycarbonylethyl)piperazine

[4023] In the same manner as in Referential Example 220, the titlecompound was obtained.

[4024]¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 1.30-1.80 (3H, m),2.30-2.45 (2H, m), 2.55-2.65 (1H, m), 2.75-3.05 (4H, m), 3.70-3.80 (2H,m), 4.11 (2H, q, J=7.2 Hz), 7.35-7.50 (4H, m), 7.50-7.60 (2H, m), 8.02(2H, d, J=7.3 Hz), 8.22 (1H, d, J=9.3 Hz).

[4025] MS (FAB) m/z: 540 [(M+H)⁺, Cl³⁵], 542 [(M+H)⁺, Cl³⁷].

Referential Example 4651,4-Bis(tert-butoxycarbonyl)-2-(2-cyanoethyl)piperazine

[4026] To an aqueous solution (3.0 ml) of potassium cyanide (85.0 mg)was added a solution of1,4-bis(t-butoxycarbonyl)-2-(2-bromoethyl)piperazine (393 mg) in ethanol(3.0 ml), followed by stirring under heat at 110° C. for 3 hours. Afterthe removal of ethanol by distillation under reduced pressure, methylenechloride (100 ml) was added to the residue. The organic layer was washedwith distilled water until the water phase became neutral. The resultingorganic layer was washed with saturated aqueous NaCl solution, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was subjected to chromatography on a silica gel column(silica gel 15 g, hexane:ethyl acetate=2:1), whereby the title compound(145.0 mg, 43%) was obtained as a white solid.

[4027]¹H-NMR (CDCl₃) δ: 1.47 (12H, s), 1.49 (6H, s), 1.75-1.88 (1H, m),1.92-2.10 (1H, m), 2.28-2.35 (2H, m), 2.70-3.10 (3H, m), 3.80-4.15 (3H,m), 4.20-4.30 (1H, m).

[4028] MS (FAB) m/z: 340 (M+H)⁺.

Referential Example 4664-[(1-Phenylsulfonyl-5-chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)piperazine

[4029] In the same manner as in Referential Example 220, the titlecompound was obtained.

[4030]¹H-NMR (DMSO-d₆) δ: 1.65-1.77 (1H, m), 1.78-1.90 (1H, m), 2.48(2H, t, J=7.6 Hz), 2.70 (1H, dd, J=12.5, 9.5 Hz), 2.85-3.10 (4H, m),3.62-3.70 (1H, m), 3.75-3.85 (1H, m), 7.40-7.50 (4H, m), 7.55-7.60 (2H,m), 8.01 (2H, dd, J=8.6, 1.2 Hz), 8.22 (1H, d, J=9.0 Hz).

[4031] MS (FAB) m/z: 493 [(M+H)⁺, Cl³⁵], 495 [(M+H)⁺, Cl³⁷].

Referential Example 4672-Amino-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazole

[4032] In a 200-ml egg-plant type flask, 1,4-cyclohexanedione ethyleneketal (7.80 g) was charged and dissolved in cyclohexane (20 mL). To theresulting solution were added pyrrolidine (4.35 mL) andp-toluenesulfonic acid monohydrate (48.0 g), followed by heating underreflux while water was trapped by a Dean and Stark apparatus. After 70minutes, the reaction mixture was cooled to room temperature and thesolvent was decanted and concentrated under reduced pressure. Theresidue was dissolved in methanol (15 ml). While attention was paid soas not to occur a temperature rise due to water bath, sulfur powder(1.60 g) was added to the resulting solution. After 15 minutes, asolution of cyanamide (2.10 g) in methanol (10 mL) was added dropwiseover 20 minutes. After 14 hours, the solvent was distilled off underreduced pressure. The residue was subjected to chromatography on asilica gel column (silica gel: 300 g, methylenechloride:methanol=100:5→10:1), whereby the title compound (8.89 g) wasobtained as a dark green solid.

[4033]¹H-NMR (CDCl₃) δ: 1.96 (2H, t, J=6.4 Hz), 2.74 (2H, t, J=6.4 Hz),2.81 (2H, s), 4.02 (4H, s), 4.77 (2H, br s).

[4034] MS (FAB) m/z: 213 (M+H)⁺.

Referential Example 4682-Chloro-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazole

[4035] Copper (II) chloride (760 mg) was charged in a 100-mL egg-planttype flask and dissolved in acetonitrile (10 mL). While cooling overwater bath, tert-butyl nitrite (730 mg) was added in one portion to theresulting solution. After 10 minutes,2-amino-6,6-ethylenedioxy-4,5,6,7-tetahydrobenzo[d]thiazole (1.00 g) wasadded over about 50 minutes, followed by stirring at room temperaturefor 1 hour. The reaction mixture was then heated to 65° C. and stirringwas continued for 2 hours. After silica gel (5 g) was added to thereaction mixture, the solvent was distilled off under reduced pressure.The residue was purified by chromatography on a silica gel column(silica gel: 50 g, hexane:ethyl acetate=3:1), whereby the title compound(860 mg) was obtained as a yellow oil.

[4036]¹H-NMR (CDCl₃) δ: 2.00 (2H, t, J=6.4 Hz), 2.91 (4H, m), 4.03 (4H,s).

[4037] MS (FAB) m/z: 232 [(M+H)⁺, Cl³⁵], 234 [(M+H)⁺, Cl³⁷].

Referential Example 4696,6-Ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazole

[4038] In a 100-mL egg-plant type flask,2-chloro-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazole (860 mg)was charged and was dissolved in methanol (10 mL). To the resultingsolution were added 10% palladium-carbon (100 mg) and sodium acetate(305 mg), followed by stirring under a hydrogen gas stream of 4.5atmospheric pressure. After 17 hours, palladium was filtered off and thesolvent was distilled off under reduced pressure. The residue wassubjected to chromatography on a silica gel column (silica gel: 50 g,ethyl acetate:hexane=1:1), whereby the title compound (720 mg) wasobtained as a pale yellow oil.

[4039]¹H-NMR (CDCl₃) δ: 2.04 (2H, t, J=6.8 Hz), 3.03 (4H, m), 4.05 (4H,s), 8.62 (1H, s).

[4040] MS (FAB) m/z: 198 (M+H)⁺.

Referential Example 470 Lithium(6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carboxylate

[4041] In the same manner as in Referential Example 371, the titlecompound was obtained.

[4042]¹H-NMR (DMSO-d₆) δ: 1.94 (2H, t, J=6.6 Hz), 3.34-3.44 (4H, m),3.95 (4H, s).

Referential Example 471 2-Amino-4,5-dihydro-7H-pyrano[4,3-d]thiazole

[4043] In the same manner as in Referential Example 467, the titlecompound was obtained.

[4044]¹H-NMR (CDCl₃) δ: 2.66-2.70 (2H, m), 3.97 (2H, t, J=5.6 Hz), 4.63(2H, s), 4.94 (2H, br s).

[4045] MS (FAB) m/z: 157 (M+H)⁺.

Referential Example 472 2-Chloro-4,5-dihydro-7H-pyrano[4,3-d]thiazole

[4046] In the same manner as in Referential Example 468, the titlecompound was obtained.

[4047]¹H-NMR (CDCl₃) δ: 2.85-2.89 (2H, m), 4.02 (2H, t, J=5.6 Hz), 4.73(2H, s).

[4048] MS (FAB) m/z: 175 [(M+H)⁺, Cl³⁵], 177 [(M+H)⁺, Cl³⁷].

Referential Example 473 4,5-Dihydro-7H-pyrano[4,3-d]thiazole

[4049] In the same manner as in Referential Example 469, the titlecompound was obtained.

[4050]¹H-NMR (CDCl₃) δ: 2.97-3.01 (2H, m), 4.04 (2H, t, J=5.6 Hz), 4.87(2H, s), 8.69 (1H, s).

[4051] MS (FAB) m/z: 142 (M+H)⁺.

Referential Example 474 Lithium(4,5-dihydro-7H-pyrano[4,3-d]thiazol-2-yl)carboxylate

[4052] In a 200-mL three-necked flask,4,5-dihydro-7H-pyrano[4,3-d]thiazole (1.14 g) was added and dissolved inether (30 mL). After cooling to −78° C., 1.6M butyl lithium (6.6 mL) wasadded and the resulting mixture was stirred. After 20 minutes, a carbondioxide gas was introduced. After about 15 minutes, the introduction wasterminated. The reaction mixture was allowed to rise back to roomtemperature and concentrated under reduced pressure, whereby the titlecompound (1.65 g) was obtained as a colorless amorphous substance.

[4053]¹H-NMR (DMSO-d₆) δ: 2.83 (2H, t, J=5.6 Hz), 3.92 (2H, t, J=5.6Hz), 4.73 (2H, s).

Referential Example 4754-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(phenylsulfonyl)carbamoyl]methyl]piperazineTrifluoroacetate

[4054] In tetrahydrofuran (10 ml) was dissolved1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(1.00 g), followed by the addition of carbonyldiimidazole (1.06 g). Theresulting mixture was heated overnight under reflux. After cooling toroom temperature, the reaction mixture was added with benzenesulfonamide(685 mg), 1,8-diazabicyclo[5.4.0]-7-undecene (0.64 ml) andcarbonyldiimidazole (353 mg). The resulting mixture was heated underreflux for 1 hour. The reaction mixture was then concentrated underreduced pressure. Dichloromethane was added to the residue and the solidthus precipitated was filtered off. The filtrate was washed successivelywith 1N hydrochloric acid and saturated aqueous NaCl solution. Theorganic layer was dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (Φ 3.0×10.0 cm,dichloromethane:methanol=100:1), whereby pale brown foam was obtained.The resulting foam was dissolved in dichloromethane (10 ml), followed bythe addition of trifluoroacetic acid (10 ml). After stirring at roomtemperature for 1 minute, the reaction mixture was concentrated underreduced pressure. Diethyl ether was added to the residue and theresulting precipitate was collected by filtration, whereby the titlecompound (496 mg, 31%) was obtained as colorless foam.

[4055]¹H-NMR (DMSO-d₆) δ: 2.60-2.75 (3H, m), 3.10-3.20 (1H, m),3.29-3.38 (1H, m), 3.53-3.73 (4H, m), 7.06 (1H, d, J=2.0 Hz), 7.34 (1H,dd, J=8.8, 2.0 Hz), 7.50 (1H, d, J=8.8 Hz), 7.64 (2H, t, J=7.1 Hz), 7.74(1H, t, J=7.1 Hz), 7.80 (1H, d, J=2.0 Hz), 7.93 (2H, d, J=7.1 Hz), 12.53(1H, s).

[4056] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Referential Example 4761-tert-Butoxycarbonyl-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N-methylsulfonylcarbamoyl)methyl]piperazine

[4057] In tetrahydrofuran (10 ml) was dissolved1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(1.00 g), followed by the addition of carbonyldiimidazole (1.06 g). Theresulting mixture was heated overnight under reflux. After cooling toroom temperature, methanesulfonamide (415 mg) and1,8-diazabicyclo[5.4.0]-7-undecene (0.64 ml) were added, followed bystirring at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure. Dichloromethane was added to theresidue and the resulting mixture was washed successively with 1Nhydrochloric acid, and saturated aqueous NaCl solution. The organiclayer was dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (φ 3.0×10.0 cm,dichloromethane:methanol=100:1), whereby the title compound (518 mg,44%) was obtained as colorless foam.

[4058]¹H-NMR (DMSO-d₆) δ: 1.33 (9H, s), 2.23-2.60 (3H, m), 2.62-2.78(1H, m), 3.05 (1H, br, s), 3.21 (3H, s), 3.52-3.70 (2H, m), 3.84-3.97(1H, m), 4.56 (1H, br s), 7.02 (1H, s), 7.32 (1H, d, J=8.8 Hz), 7.49(1H, J=8.8 Hz), 7.77 (1H, s), 11.84 (1H, s), 12.43 (1H, s).

[4059] MS (FAB) m/z: 557 [(M+Na)⁺, Cl³⁵], 559 [(M+Na)⁺, Cl³⁷].

Referential Example 4771-[(5-Chloroindol-2-yl)sulfonyl]-3-[(N-methyl-N-methylsulfonylcarbamoyl)methyl]piperazineTrifluoroacetate

[4060] In N,N-dimethylformamide (10 ml) was dissolved1-tert-butoxycarbonyl-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N-methylsulfonylcarbamoyl)methyl]piperazine(347 mg), followed by the addition of sodium bicarbonate (55 mg) andmethyl iodide (0.05 ml). The resulting mixture was stirred overnight atroom temperature. The reaction mixture was then concentrated underreduced pressure. Dichloromethane was added to the residue and theresulting mixture was washed successively with water and saturatedaqueous NaCl solution, each once. The organic layer was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (Φ 1.7×12.0 cm, dichloromethane:methanol=200:1), whereby thetitle compound was obtained as colorless foam. The resulting foam wasdissolved in dichloromethane (1 ml), followed by the addition oftrifluoroacetic acid (2 ml). After the resulting mixture was stirred atroom temperature for 1 minute, the reaction mixture was concentratedunder reduced pressure. Diethyl ether was added to the residue and theprecipitate so formed was collected by filtration, whereby the titlecompound (189 mg, 43%) was obtained as colorless foam.

[4061]¹H-NMR (DMSO-d₆) δ: 2.60-2.80 (2H, m), 3.02-3.11 (2H, m), 3.16(3H, s), 3.20-3.30 (1H, m), 3.39 (3H, s), 3.61-3.80 (4H, m), 7.08 (1H,d, J=1.5 Hz), 7.34 (1H, dd, J=8.8, 2.0 Hz), 7.50 (1H, J=8.8 Hz), 7.80(1H, d, J=2.2 Hz), 12.54 (1H, br s).

[4062] MS (FAB) m/z: 449 [(M+H)⁺, Cl³⁵], 451 [(M+H)⁺, Cl³⁷].

Referential Example 478 N-methanesulfonylhydrazine Hydrochloride

[4063] In pyridine (30 ml) was dissolved t-butyl carbazate (2.64 g),followed by the addition of methanesulfonyl chloride (1.62 ml) under icecooling. The resulting mixture was stirred at room temperature for 5hours. The reaction mixture was concentrated under reduced pressure.Ethyl acetate was added to the residue and the resulting mixture waswashed successively with 1N hydrochloric acid and a saturated aqueoussolution of sodium bicarbonate. The organic layer was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was solidified by the addition of hexane andethyl acetate, whereby a pale yellow solid was obtained. The solid wasdissolved in dichloromethane (20 ml), followed by the addition ofsaturated solution of hydrochloride in ethanol (20 ml). The resultingmixture was then concentrated under reduced pressure. The residue wassolidified by the addition of ethyl acetate, wherebyN-methanesulfonylhyrazine (1.67 g, 57%) was obtained as a pale yellowsolid.

[4064]¹H-NMR (DMSO-d₆) δ: 3.25 (3H, s), 9.80 (br s, 9.80)

[4065] MS (FAB) m/z: 111 (M+H)⁺.

Referential Example 4794-[(5-Chloroindol-2-yl)sulfonyl]-2-[(2-methylsulfonylhydrazino)carbonylmethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineTrifluoroacetate

[4066] In dichloromethane (20 ml) were dissolved1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(600 mg), N-methanesulfonylhydrazine (192 mg), 1-hydroxybenzotriazolemonohydrate (200 mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (301 mg), followed by the addition of triethylamine (0.21ml). The resulting mixture was stirred overnight at room temperature.The reaction mixture was then concentrated under reduced pressure. Ethylacetate was added to the residue and the resulting mixture was washedwith water and saturated aqueous NaCl solution, each once. The organiclayer was dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (Φ 3.0×8.0 cm,dichloromethane:methanol=50:1), whereby colorless foam was obtained. Theresulting foam was dissolved in dichloromethane (2 ml), followed by theaddition of trifluoroacetic acid (10 ml). After the resulting mixturewas stirred at room temperature for 1 minute, the reaction mixture wasconcentrated under reduced pressure. Diethyl ether was added to theresidue and the precipitate so formed was collected by filtration,whereby the title compound (278 mg, 38%) was obtained as colorless foam.

[4067]¹H-NMR (DMSO-d₆) δ: 2.51-2.82 (3H, m), 2.96 (3H, s), 3.11-3.21(1H, m), 3.31-3.42 (1H, m), 3.60-3.85 (4H, m), 7.07 (1H, s), 7.34 (1H,dd, J=8.8, 2.0 Hz), 7.50 (1H, J=8.8 Hz), 7.80 (1H, s), 9.52 (1H, d,J=2.7 Hz), 10.39 (1H, d, J=2.7 Hz), 12.51-12.57 (1H, m).

[4068] MS (FAB) m/z: 450 [(M+H)⁺, Cl³⁵], 452 [(M+H)⁺, Cl³⁷].

Referential Example 4801-(tert-Butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(pyrrolidin-1-ylcarbonyl)methyl]piperazine

[4069] The title compound was obtained by employing the method ofReferential Example 319 in which1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride had been usedas a condensing agent.

[4070]¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.85-1.97 (2H, m), 1.98-2.18 (2H,m), 2.22-2.35 (1H, m), 2.50-3.00 (3H, m), 2.97 (1H, dt, J=3.4, 13.0 Hz),3.40-3.60 (4H, m), J=3.64-3.75 (1H, m), 3.80-4.20 (2H, m), 4.63 (1H, brd, J=10.0 Hz), 6.96 (1H, d, J=1.7 Hz), 7.27 (1H, dd, J=9.1, 1.7 Hz),7.37 (1H, d, J=9.1 Hz), 7.65 (1H, d, J=1.7 Hz).

[4071] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Referential Example 4812-[(N-Benzylcarbamoyl)methyl]-1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[4072] The title compound was obtained by employing the method ofReferential Example 319 in which1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride had been usedas a condensing agent.

[4073]¹H-NMR (CDCl₃) δ: 1.40 (9H, s), 2.35-2.48 (1H, m), 2.50-2.85 (3H,m), 2.95-3.07 (1H, m), 3.62-3.78 (1H, m), 3.80-4.15 (2H, m), 4.40-4.50(2H, m), 4.60-4.70 (1H, m), 6.93 (1H, s), 7.20-7.40 (7H, m), 7.64 (1H,s).

[4074] MS (FAB) m/z: 547 [(M+H)⁺, Cl³⁵], 549 [(M+H)⁺, Cl³⁷].

Referential Example 482 5(6)-chloro-2-mercaptobenzimidazole

[4075] Carbon disulfide (6.60 ml) and sodium hydroxide (6.330 g) wereadded to the mixture of 4-chloro-1,2-phenylenediamine (14.37 g), ethanol(100 ml) and water (15 ml), and reacted under reflux for 3 hours. Thereaction mixture was added by active carbon (4.0 g), refluxed for 10minutes, and filtrated by means of suction. The precipitated substanceswere washed with ethanol (100 ml) and 70° C. hot water (200 ml) toobtain a solution. The obtained solution was added to the mixture ofacetic acid (9.0 ml) and water (16.0 ml), concentrated under reducedpressure, purified by chromatography on a silica gel column (ethylacetate), and solidified by acetone-water and ethyl acetate-hexane,followed by drying. Thus, the title compound (9.03 g) was obtained aspale yellow powder.

[4076] m.p. >220% (dec)

[4077] IR (KBr) cm⁻¹ 3116, 3084, 3055, 2952, 1614, 1512, 1475, 1369,1323, 1190, 1066.

[4078]¹H-NMR (CD₃OD) d 7.15 (2H, s), 7.21 (1H, s).

[4079] MS (EI) m/z 184 [M⁺, C¹³⁵], 186 [M⁺, C¹³⁷].

Referential Example 4831-(tert-butoxycarbonyl)-4-[[5(6)-chlorobenzimidazol-2-yl]sulfonyl]piperazine

[4080] 5(6)-chloro-2-mercaptobenzimidazole (1.837 g) was suspended in a20% solution of acetic acid, and then blown by a chloride gas at atemperature less than 7° C. for 70 minutes. Yellow precipitates wereobtained by filtration and thereafter, washed with cold water. Theobtained yellow solid was added to the mixture of1-(tert-butoxycarbonyl)piperazine (3.905 g), water (18 ml) and acetone(20 ml), and stirred at room temperature for 20 hours. After discardingthe acetone, precipitates were filtered and dried, whereby the titlecompound (3.16 q) was obtained as pale yellow powder.

[4081] m.p. 210-211° C.

[4082] IR (KBr) cm⁻¹ 3212, 2983, 1666, 1435, 1367, 1356, 1279, 1176,1165, 1147, 1138, 974, 949.

[4083]¹H-NMR (CDCl₃) d 1.44 (9H, s), 3.33-3.41 (4H, m), 3.53-3.59 (4H,m), 7.30-7.60 (2H, m), 7.72-7.88 (1H, m).

[4084] MS (FAB) m/z 401 [(M⁺+H)⁺, C¹³⁵], 403 [(M⁺+H)⁺, C¹³⁷].

Referential Example 4841-[[5(6)-chlorobenzimidazol-2-yl]sulfonyl]piperazine Hydrochloride

[4085] Saturated solution of hydrochloride in ethanol (5.0 ml) was addedto the mixture of1-(tert-butoxycarbonyl)-4-[[5(6)-chlorobenzimidazol-2-yl]sulfonyl]piperazine(1.406 g), ethanol (5.0 ml) and dichloromethane (4.0 ml), and thenstirred at room temperature for 4 hours. After concentration underreduced pressure, the obtained product was purified by chromatography ona silica gel column (dichloromethane:methanol=20:1). The purifiedcompound was added to 1N solution of hydrochloride in ethanol (1 ml),concentrated and dried, whereby the title compound (1.19 g) was obtainedas a hygroscopic colorless amorphous substance.

[4086]¹H-NMR (DMSO-d₆) d 3.2-5-3.80 (8H, m), 7.40-7.50 (1H, br),7.60-7.80 (2H, br), 9.20-9.55 (1H, br).

[4087] MS (FAB) m/z 301 [(M+H)⁺, C¹³⁵], 303 [(M+H)⁺, C¹³⁷].

Example A-11-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4088] At room temperature, 1-[4-(4-pyridyl)benzoyl]piperazineditrifluoroacetate (1.19 g) was suspended in dichloromethane (100 ml),followed by the addition of diisopropylethylamine (1.68 ml) and6-chloro-2-naphthylsulfonyl chloride (WO/96/10022) (691 mg). Afterstirring at room temperature for 2 hours, the reaction mixture waspurified by chromatography on a silica gel column (2%methanol—dichloromethane). To the resulting fraction, 1N hydrochloricacid in ethanol was added to make it weakly acidic. The solvent was thendistilled off. The resulting colorless solid was washed withtetrahydrofuran, whereby the title compound (1.05 g, 81%) was obtainedas a colorless solid.

[4089]¹H-NMR (DMSO-d₆) δ: 2.95-3.25 (4H, m), 3.43 (2H, br s), 3.60 (2H,br s), 7.56 (2H, d, J=8.3 Hz), 7.74 (1H, dd, J=8.8, 2.5 Hz), 7.83 (1H,dd, J=8.8, 2.0 Hz), 8.01 (2H, d, J=8.3 Hz), 8.19 (1H, d, J=8.8 Hz),8.25-8.40 (4H, m), 8.51 (1H, s), 8.94 (2H, d, J=6.8 Hz).

[4090] MS (FAB) m/z: 492 [(M+H)⁺, Cl³⁵], 494 [(M+H)⁺, Cl³⁷].

[4091] Elementary analysis for C₂₆H₂₂N₃O₃ClS.HCl.0.5H₂O

[4092] Calculated: C, 58.10; H, 4.50; N, 7.82; Cl, 13.19; S, 5.97.

[4093] Found: C, 58.12; H, 4.67; N, 7.66; Cl, 13.12; S, 6.10.

Example A-24-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4094] In dichloromethane (30 ml),4-tert-butoxycarbonyl-2-ethoxycarbonyl-1-[4-(4-pyridyl)benzoyl]piperazine(514 mg) was dissolved, followed by the addition of trifluoroacetic acid(30 ml) under ice cooling. After stirring at room temperature for 45minutes, the residue obtained by distilling off the solvent wassuspended in dichloromethane (100 ml) under ice cooling, followed by theaddition of diisopropylethylamine (1.02 ml) and6-chloro-2-naphthylsulfonyl chloride (WO96/10022) (366 mg). Afterstirring at room temperature for one hour, the reaction mixture waspurified as was by chromatography on a silica gel column (1%methanol—dichloromethane). To the resulting fraction, 1N hydrochloricacid in ethanol was added to make it weakly acidic. The solvent was thendistilled off. The resulting colorless solid was washed with ethanol,whereby the title compound (308 mg, 43%) was obtained as a colorlesssolid.

[4095]¹H-NMR (DMSO-d₆) δ: 1.15-1.30 (3H, m), 2.60-5.40 (9H, m), 7.50(⅔H, d, J=8.3 Hz), 7.57 ({fraction (4/3)}H, d, J=7.8 Hz), 7.74 (1H, dd,J=9.0, 1.7 Hz), 7.83 (1H, d, J=8.8 Hz), 8.00 (⅔H, d, J=7.8 Hz), 8.04({fraction (4/3)}H, d, J=8.3 Hz), 8.19 (1H, d, J=8.8 Hz), 8.25-8.35 (4H,m), 8.55 (1H, s), 8.92 (2H, d, J=4.9 Hz).

[4096] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁷].

[4097] Elementary analysis for C₂₉H₂₆N₃O₅ClS.HCl.0.5H₂O

[4098] Calculated: C, 57.15; H, 4.63; N, 6.89; Cl, 11.63; S, 5.26.

[4099] Found: C, 56.95; H, 4.68; N, 6.70; Cl, 11.36; S, 5.30.

Example A-3

[4100]4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine-2-carboxylicAcid Hydrochloride

[4101] In a mixed solvent of ethanol (1 ml), tetrahydrofuran (1 ml) andwater (1 ml),4-[(6-chloronaphthalen-2-yl)sulfonyl-2-ethoxycarbonyl-1-[4-(pyridin-4-yl)benzoyl]piperazinehydrochloride (152 mg) obtained in Example A-2 was dissolved under icecooling, followed by the dropwise addition of a 1N aqueous solution ofsodium hydroxide. The reaction mixture was stirred at room temperaturefor 90 minutes. After concentration under reduced pressure, 1Nhydrochloric acid was added to the reaction mixture to make it weaklyacidic. The colorless solid so precipitated was collected by filtration,followed by drying, whereby the title compound (62 mg, 42%) was obtainedas a colorless solid.

[4102]¹H-NMR (DMSO-d₆) δ: 2.65-5.30 (7H, m), 7.49 (⅘H, d, J=7.7 Hz),7.56 ({fraction (6/5)}H, d, J=8.3 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz),7.82 (1H, d, J=8.3 Hz), 7.95-8.05 (2H, m), 8.19 (1H, d, J=8.3 Hz),8.20-8.35 (4H, m), 8.53 (1H, s), 8.92 (2H, d, J=5.4 Hz).

[4103] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

[4104] Elementary analysis for C₂₇H₂₂N₃O₅ClS.0.9HCl.1.2H₂O

[4105] Calculated: C, 54.92; H, 4.32; N, 7.12; Cl, 11.41; S, 5.43.

[4106] Found: C, 54.94; H, 4.42; N, 6.83; Cl, 11.31; S, 5.33.

Example A-4

[4107]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)nicotinyl]piperazineHydrochloride

[4108] In dichloromethane (10 ml), 6-(4-pyridyl)nicotinic acidhydrochloride (96 mg) and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate (150mg) were suspended, followed by the addition of 1-hydroxybenzotriazole(48 mg) and N-methylmorpholine (155 μl). After the addition of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102 mg)under ice cooling, the resulting mixture was stirred at room temperaturefor 16 hours. Owing to the slow reaction, N,N-dimethylformamide (10 ml)was added to the reaction mixture and the resulting mixture was stirredfor 3 days. After completion of the reaction, the solvent was distilledoff. The residue was purified by chromatography on a silica gel column(1% methanol—dichloromethane). The solvent was then distilled off. Tothe residue, tetrahydrofuran and 1N hydrochloric acid in ethanol wereadded and the solid so precipitated was collected by filtration anddried, whereby the title compound (105 mg, 55%) was obtained as acolorless solid.

[4109]¹H-NMR (DMSO-d₆) δ: 3.00-3.25 (4H, m), 3.46 (2H, br s), 3.76 (2H,br s), 7.74 (1H, dd, J=8.5, 1.7 Hz), 7.83 (1H, d, J=8.8 Hz), 8.07 (1H,dd, J=7.8, 1.5 Hz), 8.19 (1H, d, J=8.8 Hz), 8.28 (1H, s), 8.29 (1H, d,J=8.8 Hz), 8.42 (1H, d, J=8.3 Hz), 8.51 (1H, s), 8.65 (2H, d, J=6.4 Hz),8.80 (1H, m), 9.01 (2H, d, J=5.9 Hz).

[4110] MS (FAB) m/z: 493 [(M+H)⁺, Cl³⁵], 495 [(M+H)⁺, Cl³⁷].

[4111] Elementary analysis for C₂₅H₂₁N₄O₃ClS.HCl.H₂O

[4112] Calculated: C, 54.85; H, 4.42; N, 10.23; Cl, 12.95; S, 5.86.

[4113] Found: C, 54.57; H, 4.51; N, 10.06; Cl, 13.08; S, 5.87.

Example A-51-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-3-yl)benzoyl]piperazineHydrochloride

[4114] In the same manner as in Example A-4, a reaction was conductedusing 4-(3-pyridyl)benzoic acid hydrochloride and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate asstarting materials, whereby the title compound was obtained as acolorless solid.

[4115]¹H-NMR (DMSO-d₆) δ: 3.00-3.25 (4H, m), 3.47 (2H, br s), 3.73 (2H,br s), 7.51 (2H, d, J=8.3 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.8-7.9(3H, m), 7.92 (1H, dd, J=7.8, 5.4 Hz), 8.19 (1H, d, J=8.8 Hz), 8.25-8.30(2H, m), 8.50 (1H, s), 8.55-8.65 (1H, m), 8.75-8.85 (1H, m), 9.14 (1H,d, J=2.0 Hz).

[4116] MS (FAB) m/z: 492 [(M+H)⁺, Cl³⁵], 494 [(M+H)⁺, Cl³⁷].

[4117] Elementary analysis for C₂₆H₂₂N₃O₃ClS.0.85HCl.H₂O

[4118] Calculated: C, 57.72; H, 4.63; N, 7.77; Cl, 12.12; S, 5.93.

[4119] Found: C, 57.44; H, 4.62; N, 7.68; Cl, 11.99; S, 5.83.

Example A-64-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4120] In dichloromethane (10 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine(300 mg) obtained in Example A-1 was dissolved, followed by the additionof 3-chloroperbenzoic acid (382 g) at −20° C. The resulting mixture wasstirred at −20° C. for 21 hours. An aqueous solution of sodium sulfitewas added to decompose an excess peroxide. Dichloromethane and asaturated aqueous solution of sodium bicarbonate were added to separatean organic layer. After drying the organic layer over anhydrousmagnesium sulfate, the residue obtained by distilling off the solventwas purified by chromatography on a silica gel column (2-5%methanol—dichloromethane). After the solvent was distilled off, etherwas added to the residue to solidify it, followed by collection throughfiltration, whereby the title compound (200 mg, 63%) was obtained as acolorless solid.

[4121]¹H-NMR (CDCl₃) δ: 2.90-3.40 (4H, m), 3.40-4.20 (4H, m), 7.43 (2H,d, J=8.3 Hz), 7.47 (2H, d, J=7.3 Hz), 7.55-7.65 (3H, m), 7.76 (1H, dd,J=8.8, 10.5 Hz), 7.90-8.00 (3H, m), 8.26 (2H, d, J=7.3 Hz), 8.31 (1H,s).

[4122] MS (FAB) m/z: 508 [(M+H)⁺, Cl³⁵], 510 [(M+H)⁺, Cl³⁷].

[4123] Elementary analysis for C₂₆H₂₂N₃O₄ClS.0.8H₂O

[4124] Calculated: C, 59.78; H, 4.55; N, 8.04; Cl, 6.79; S, 6.14.

[4125] Found: C, 59.82; H, 4.45; N, 7.94; Cl, 6.85; S, 6.29.

Example A-71-[4-(2-Aminopyridin-5-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4126] In a mixed solvent of dichloromethane (1 ml) and ethanol (1 ml),1-[4-[2-tert-butoxycarbonylamino]pyridin-5-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(128 mg) was dissolved, followed by the addition of a saturatedhydrochloride solution in ethanol (10 ml) under ice cooling. Afterstirring at room temperature for 1 minute, the solvent was distilledoff. Isopropanol was added to the residue for crystallization. Thecrystals so obtained were collected by filtration and dried, whereby thetitle compound (88 mg, 68%) was obtained as a colorless solid.

[4127]¹H-NMR (DMSO-d₆) δ: 3.00-3.20 (4H, m), 3.30-3.90 (4H, m), 7.05(½H, d, J=8.8 Hz), 7.06 (½H, d, J=8.8 Hz), 7.43 (2H, d, J=8.3 Hz), 7.67(2H, d, J=8.3 Hz), 7.73 (1H, d, J=8.3 Hz), 7.82 (1H, d, J=8.8 Hz),7.90-8.10 (2H, br), 8.18 (1H, d, J=8.3 Hz), 8.25-8.35 (4H, m), 8.50 (1H,s).

[4128] MS (FAB) m/z: 507 [(M+H)⁺, Cl³⁵], 509 [(M+H)⁺, Cl³⁷].

[4129] Elementary analysis for C₂₆H₂₃ClN₄O₃S.HCl.1.2H₂O.0.81PrOH

[4130] Calculated: C, 55.56; H, 5.52; N, 9.13; Cl, 11.55; S, 5.22.

[4131] Found: C, 55.40; H, 5.24; N, 8.85; Cl, 11.79; S, 5.50.

Example A-81-[4-(4-Aminophenyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4132] In the same manner as in Example A-7, a reaction was conductedusing1-[4-[4-(tert-butoxycarbonylamino)phenyl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material, whereby the title compound was obtained as acolorless solid.

[4133]¹H-NMR (DMSO-d₆) δ: 2.90-3.20 (4H, m), 3.25-3.80 (4H, m), 6.68(2H, d, J=8.3 Hz), 7.32 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.54(2H, d, J=8.3 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8,2.0 Hz), 8.18 (1H, dd, J=8.8 Hz), 8.25-8.40 (2H, m), 8.50 (1H, br s).

[4134] MS (FAB) m/z: 506 [(M+H)⁺, Cl³⁵], 508 [(M+H)⁺, Cl³⁷].

[4135] Elementary analysis for C₂₇H₂₄ClN₃O₃S.0.2HCl

[4136] Calculated: C, 63.18; H, 4.75; N, 8.19; Cl, 8.29; S, 6.25.

[4137] Found: C, 62.93; H, 4.93; N, 7.91; Cl, 7.99; S, 6.36.

Example A-91-[4-(2-Aminothiazol-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4138] In the same manner as in Example A-4, a reaction was effectedusing 4-(2-aminothiazol-4-yl)benzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4139]¹H-NMR (DMSO-d₆) δ: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m), 7.26(1H, s), 7.41 (2H, d, J=8.3 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.79 (2H,d, J=8.3 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.18 (1H, d, J=8.8 Hz),8.25-8.30 (2H, m), 8.50 (1H, br s).

[4140] MS (FAB) m/z: 513 [(M+H)⁺, Cl³⁵], 515 [(M+H)⁺, Cl³⁷].

[4141] Elementary analysis for C₂₄H₂₁N₄O₃ClS₂.HCl.0.3H₂O

[4142] Calculated: C, 51.95; H, 4.11; N, 10.10; Cl, 12.78; S, 11.56.

[4143] Found: C, 51.99; H, 4.19; N, 10.03; Cl, 12.61; S, 11.45.

Example A-101-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4[-imidazol-4(5)-yl]benzoyl]piperazineHydrochloride

[4144] In dichloromethane (5 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-[1-triphenylmethylimidazol-4(5)-yl]benzoyl]piperazine(303 mg) was dissolved, followed by the addition of a saturatedhydrochloride solution in ethanol (30 ml) under ice cooling. Afterstirring at room temperature for 3 hours, the solvent was distilled off.Ether was added to the residue for crystallization and the resultingcrystals were collected by filtration, whereby the title compound (307mg, 76%) was obtained as a colorless solid.

[4145]¹H-NMR (DMSO-d₆) δ: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m), 7.47(2H, d, J=8.3 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8,2.0 Hz), 7.89 (2H, d, J=8.3 Hz), 8.19 (1H, d, J=8.8 Hz), 8.22 (1H, d,J=1.0 Hz), 8.25-8.30 (2H, m), 8.50 (1H, m), 9.22 (1H, d, J=1.0 Hz).

[4146] MS (FAB) m/z: 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

[4147] Elementary analysis for C₂₄H₂₁ClN₄O₃S.HCl.0.4H₂O

[4148] Calculated: C, 54.94; H, 4.38; N, 10.68; Cl, 13.52; S, 6.11.

[4149] Found: C, 54.98; H, 4.29; N. 10.62; Cl. 13.56; S, 6.14.

Example A-111-[4-(2-Aminoimidazol-4-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4150] In the same manner as in Example A-4, a reaction was conductedusing 4-[2-aminoimidazol-4-yl]benzoic acid hydrochloride and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4151]¹H-NMR (DMSO-d₆) δ: 2.90-3.20 (4H, m), 3.30-3.90 (4H, m), 7.39(2H, d, J=8.3 Hz), 7.47 (1H, s), 7.49 (2H, br s), 7.67 (2H, d, J=8.3Hz), 7.73 (1H, dd, J=8.8, 2.5 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.18(1H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.50 (1H, br s).

[4152] MS (FAB) m/z: 496 [(M+H)⁺, Cl³⁵], 498 [(M+H)⁺, Cl³⁷].

[4153] Elementary analysis for C₂₄H₂₂N₅O₃ClS.HCl

[4154] Calculated: C, 54.14; H, 4.35; N, 13.15; Cl, 13.32; S, 6.02.

[4155] Found: C, 53.94; H, 4.39; N, 12.82; Cl, 13.27; S, 6.07.

Example A-124-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-1-methylpyridiniumIodide

[4156] In a mixed solvent of benzene (10 ml) and methanol (10 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine(300 mg) obtained in Example A-1 was dissolved at room temperature,followed by the addition of methyl iodide (1 ml). To the resultingmixture, the same amount of methyl iodide was added three times atintervals of 24 hours, followed by heating under reflux for 4 days. Thereaction mixture was distilled under reduced pressure and the residuewas washed with methanol, collected by filtration and dried, whereby thetitle compound (229 mg, 58%) was obtained as a yellow solid.

[4157]¹H-NMR (DMSO-d₆) δ: 3.03 (2H, br s), 3.13 (2H, br s), 3.43 (2H, brs), 3.75 (2H, br s), 4.34 (3H, s), 7.59 (2H, d, J=8.8 Hz), 7.74 (1H, dd,J=8.8, 2.4 Hz), 7.85 (1H, dd, J=8.8, 2.0 Hz), 8.08 (2H, d, J=8.8 Hz),8.19 (1H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.45-8.55 (3H, m), 9.03 (2H,d, J=6.8 Hz).

[4158] Elementary analysis for C₂₇H₂₅N₃O₃ClIS.H₂O

[4159] Calculated: C, 49.74; H, 4.17; N, 6.45.

[4160] Found: C, 49.60; H, 4.09; N, 6.23.

Example A-133-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4161] In the same manner as in Example A-6, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-3-yl)benzoyl]piperazine,which had been obtained in Example A-5, as a starting material, wherebythe title compound was obtained.

[4162]¹H-NMR (CDCl₃) δ: 2.90-3.40 (4H, m), 3.40-4.20 (4H, m), 7.50-7.60(1H, m), 7.40-7.45 (3H, m), 7.54 (2H, d, J=8.3 Hz), 7.60 (1H, dd, J=8.8,2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.90-8.00 (3H, m), 8.22 (1H, d,J=5.9 Hz), 8.31 (1H, d, J=2.0 Hz), 8.43 (1H, br s).

[4163] MS (FAB) m/z: 508 [(M+H)⁺, Cl³⁵], 510 [(M+H)⁺, Cl³⁷].

[4164] Elementary analysis for C₂₆H₂₂N₃O₄ClS.H₂O

[4165] Calculated: C, 59.37; H, 4.60; N, 7.99; Cl, 6.74; S, 6.10.

[4166] Found: C, 59.48; H, 4.69; N, 7.74; Cl, 6.73; S, 6.07.

Example A-141-[2-Carboxy-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[4167] In dichloromethane (50 ml),1-[2-tert-butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride (250 g) was dissolved, followed by the dropwise additionof trifluoroacetic acid (50 ml) under ice cooling. After stirring atroom temperature for 5 hours, the solvent was distilled off. The residuewas dissolved in methanol and the resulting solution was allowed tostand in a refrigerator for one day. The colorless solid so precipitatedwas collected by filtration and dried, whereby the title compound (550mg, 28%) was obtained as a colorless solid.

[4168]¹H-NMR (DMSO-d₆) δ: 2.90-3.40 (6H, m), 3.65-3.75 (2H, m), 7.41(1H, d, J=7.8 Hz), 7.70-7.75 (3H, m), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.00(1H, dd, J=7.8, 1.5 Hz), 8.15-8.30 (4H, m), 8.50 (1H, br s), 8.67 (2H,d, J=5.9 Hz), 13.29 (1H, br s)

[4169] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

[4170] Elementary analysis for C₂₇H₂₂ClN₃O₅S.0.5H₂O

[4171] Calculated: C, 59.50; H, 4.25; N, 7.71; Cl, 6.50; S, 5.88.

[4172] Found: C, 59.54; H, 4.30; N, 7.37; Cl, 6.35; S, 5.89.

Example A-151-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)thiophen-2-yl]carbonyl]piperazineHydrochloride

[4173] In the same manner as in Example A-4, a reaction was conductedusing 5-(pyridin-4-yl)thiophene-2-carboxylic acid hydrochloride obtainedin Referential Example 28 and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4174]¹H-NMR (DMSO-d₆) δ: 3.11 (4H, br s), 3.74 (4H, br s), 7.52 (1H, d,J=3.9 Hz), 7.73 (1H, dd, J=8.8, 2.5 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz),8.03 (1H, d, J=3.9 Hz), 8.10-8.15 (2H, m), 8.18 (1H, d, J=8.8 Hz),8.25-8.30 (2H, m), δ 8.51 (1H, s), 8.88 (2H, d, J=6.8 Hz).

[4175] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[4176] Elementary analysis for C₂₄H₂₀ClN₃O₃S₂.HCl.H₂O

[4177] Calculated: C, 52.17; H, 4.20; N, 7.61; Cl, 12.83; S, 11.61.

[4178] Found: C, 52.04; H, 4.22; N, 7.22; Cl, 12.74; S, 11.57.

Example A-161-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)furan-2-yl]carbonyl]piperazineHydrochloride

[4179] In the same manner as in Example A-4, a reaction was conductedusing 5-(pyridin-4-yl)furan-2-carboxylic acid hydrochloride obtained inReferential Example 29 and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4180]¹H-NMR (DMSO-d₆) δ: 3.13 (4H, br s), 3.30-4.00 (4H, m), 7.21 (1H,d, J=3.9 Hz), 7.71 (1H, d, J=8.8 Hz), 7.75-7.80 (1H, m), 7.83 (1H, d,J=8.8 Hz), 8.10-8.30 (5H, m), 8.51 (1H, s), 8.85-8.90 (2H, m).

[4181] MS (FAB) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

[4182] Elementary analysis for C₂₄H₂₀ClN₃O₄S HCl H₂O

[4183] Calculated: C, 53.74; H, 4.32; N, 7.83; Cl, 13.22; S, 5.98.

[4184] Found: C, 53.51; H, 4.36; N, 7.57; Cl, 13.21; S, 5.97.

Example A-171-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4185] In the same manner as in Example A-4, a reaction was conductedusing 4-(pyridin-2-yl)benzoic acid hydrochloride obtained in ReferentialExample 30 and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinehydrochloride as starting materials, whereby the title compound wasobtained.

[4186]¹H-NMR (DMSO-d₆) δ: 3.07 (4H, br), 3.60-4.00 (4H, br), 7.46 (3H,br), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz),7.94-8.05 (2H, br), 8.08 (2H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.28(2H, d, J=8.8 Hz), 8.50 (1H, s), 8.70 (1H, br).

[4187] MS (FAB) m/z: 492 [(M+H)⁺, Cl³⁵], 494 [(M+H)⁺, Cl³⁷].

[4188] Elementary analysis for C₂₆H₂₂ClN₃O₃S.0.9HCl.H₂O

[4189] Calculated: C, 57.53; H, 4.62; Cl, 12.41; N, 7.74; S, 5.91.

[4190] Found: C, 57.55; H, 4.52; Cl, 12.64; N, 7.61; S, 6.03.

Example A-181-[(E)-4-Chlorostyrylsulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4191] In the same manner as in Example A-17, a reaction was conductedusing 4-(2-pyridyl)benzoic acid hydrochloride and1-[(E)-4-chlorostyrylsulfonyl]piperazine hydrochloride as startingmaterials, whereby the title compound was obtained.

[4192]¹H-NMR (DMSO-d₆) δ: 3.19 (4H, br), 3.46 (2H, br), 3.75 (2H, br),7.36 (1H, d, J=15.6 Hz), 7.44 (1H, d, J=15.6 Hz), 7.50-7.58 (1H, br),7.53 (2H, d, J=7.8 Hz), 7.57 (2H, d, J=7.8 Hz), 7.82 (2H, d, J=7.8 Hz),8.13 (2H, m), 8.15 (2H, d, J=7.8 Hz), 8.75 (1H, d, J=4.9 Hz).

[4193] MS (FAB) m/z: 468 [(M+H)⁺, Cl³⁵], 470 [(M+H)⁺, Cl³⁷].

[4194] Elementary analysis for C₂₄H₂₂ClN₃O₃S.HCl.0.3EtOH.0.3H₂O

[4195] Calculated: C, 56.42H, 4.89; Cl, 13.54; N, 8.02; S, 6.12.

[4196] Found: C, 56.51H, 4.83; Cl, 13.46; N, 8.10; S, 5.99.

Example A-192-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4197] In the same manner as in Example A-6, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazine,which had been obtained in Example A-17, as a starting material, wherebythe title compound was obtained.

[4198]¹H-NMR (CDCl₃) δ: 3.11 (4H, br), 3.63 (2H, br), 3.87 (2H, br),7.27 (1H, m), 7.33 (1H, t, J=8.8 Hz), 7.39-7.41 (1H, br), 7.40 (2H, d,J=7.8 Hz), 7.60 (1H, d, J=8.8 Hz), 7.77 (1H, d, J=8.8 Hz), 7.83 (2H, d,J=7.8 Hz), 7.93 (1H, d, J=3.8 Hz), 7.94 (1H, s), 8.31 (1H, s), 8.33 (1H,d, J=5.9 Hz).

[4199] MS (FAB) m/z: 508 [(M+H)⁺, Cl³⁵], 510 [(M+H)⁺, Cl³⁷].

[4200] Elementary analysis for C₂₆H₂₂ClN₃O₄S

[4201] Calculated: C, 61.47; H, 4.37; Cl, 6.98; N, 8.27; S, 6.31.

[4202] Found: C, 61.32; H, 4.46; Cl, 7.21; N, 8.13; S, 6.02.

Example A-202-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-1-methylpyridiniumIodide

[4203] In the same manner as in Example A-12, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazine,which had been obtained in Example A-17, as a starting material, wherebythe title compound was obtained.

[4204]¹H-NMR (DMSO-d₆) δ: 2.93-3.23 (4H, br), 3.54 (2H, br), 3.82 (2H,br), 4.30 (3H, s), 7.50 (2H, d, J=8.8 Hz), 7.53 (1H, m), 7.70 (2H, d,J=8.8 Hz), 7.70 (1H, br), 7.84-7.92 (4H, m), 8.15 (1H, t, J=6.8 Hz),8.26 (1H, s), 8.52 (1H, t, J=6.8 Hz), 9.29 (1H, d, J=5.9 Hz).

[4205] Elementary analysis for C₂₇H₂₅ClIN₃O₃S.1.6H₂O

[4206] Calculated: C, 48.93; H, 4.29; N, 6.34.

[4207] Found: C, 48.81; H, 4.06; N, 6.31.

Example A-211-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2,4-diaminopyrimidin-6-yl)benzoyl]piperazineHydrochloride

[4208] In the same manner as in Example A-4, a reaction was conductedusing 4-(2,4-diamino-6-pyrimidyl)benzoic acid hydrochloride and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4209]¹H-NMR (DMSO-d₆) δ: 3.14 (4H, br), 3.45 (2H, br s), 3.73 (2H, brs), 6.36 (1H, s), 7.54 (2H, d, J=7.8 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz),7.82 (1H, d, J=8.8 Hz), 7.83 (1H, s), 7.84 (2H, d, J=7.8 Hz), 8.18 (1H,J=8.8 Hz), 8.18-8.35 (3H, br), 8.27 (1H, s), 8.28 (1H, d, J=8.8 Hz),8.50 (1H, s), 12.64 (1H, br s).

[4210] MS (FAB) m/z: 523 [(M+H)⁺, Cl³⁵], 525 [(M+H)⁺, Cl³⁷].

[4211] Elementary analysis for C₂₅H₂₃ClN₆O₃S.HCl.1.4H₂O

[4212] Calculated: C, 51.36; H, 4.62; Cl, 12.13; N, 14.37; S, 5.48.

[4213] Found: C, 51.38; H, 4.54; Cl, 12.24; N, 14.23; S, 5.55.

Example A-221-[(E)-4-Chlorostyrylsulfonyl]-4-[4-(2,4-diaminopyrimidin-6-yl)benzoyl]piperazineHydrochloride

[4214] In the same manner as in Example A-21, a reaction was conductedusing 4-(2,4-diamino-6-pyrimidyl)benzoic acid hydrochloride and1-[(E)-4-chlorostyrylsulfonyl)piperazine hydrochloride obtained inReferential Example 31 as starting materials, whereby the title compoundwas obtained.

[4215]¹H-NMR (DMSO-d₆) δ: 3.18 (4H, br), 3.43 (2H, br), 3.76 (2H, br),4.0 (2H, br), 6.37 (1H, s), 7.84 (2H, d, J=15.6 Hz), 7.44 (1H, J=15.6Hz), 7.53 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8 Hz), 7.82 (1H, d, J=8.8Hz), 7.88 (1H, d, J=8.8 Hz), 8.23 (1H, br s), 8.32 (1H, br s), 12.58(1H, br s).

[4216] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

[4217] Elementary analysis for C₂₃H₂₃ClN₆O₃S.1.2HCl.1.4H₂O

[4218] Calculated: C, 48.64; H, 4.79; Cl, 13.73; N, 14.80; S, 5.65.

[4219] Found: C, 48.46; H, 4.56; Cl, 13.53; N, 14.54; S, 5.72.

Example A-232-[4-[[4-[(E)-4-Chlorostyrylsulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[4220] In the same manner as in Example A-1, a reaction was conductedusing 2-[4-[(1-piperazyl)carbonyl]phenyl]pyridine N-oxide hydrochlorideand (E)-4-chlorostyrylsulfonyl chloride (WO/96/10022) as startingmaterials, whereby the title compound was obtained.

[4221]¹H-NMR (CDCl₃) δ: 3.10-3.40 (4H, br), 3.66 (2H, br), 3.89 (2H,br), 6.65 (1H, d, J=15.6 Hz), 7.28 (1H, m), 7.34 (1H, t, J=7.8 Hz),7.39-7.48 (6H, m), 7.50 (2H, d, J=7.8 Hz), 7.88 (2H, d, J=7.8 Hz), 8.34(1H, d, J=5.9 Hz).

[4222] MS (FD) m/z: 483 (M⁺, Cl³⁵), 485 (M⁺, Cl³⁷)

[4223] Elementary analysis for C₂₄H₂₂ClN₃O₄S.0.5H₂O

[4224] Calculated: C, 58.47; H, 4.70; Cl, 7.19; N, 8.52; S, 6.50.

[4225] Found: C, 58.49; H, 4.80; Cl, 7.29; N, 8.31; S, 6.34.

Example A-241-[(E)-4-Chlorostyrylsulfonyl]-4-[4(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4226] Under ice cooling, piperazine (727 mg) was dissolved indichloromethane (10 ml), followed by the addition of(E)-4-chlorostyrylsulfonyl chloride (WO96/10022) (500 mg) in portions.After stirring at room temperature for one hour, the reaction mixturewas diluted with dichloromethane (100 ml), washed with a saturatedaqueous NaCl solution solution of sodium bicarbonate, a 5% aqueoussolution of citric acid, water and saturated saline and then dried overanhydrous magnesium sulfate. The residue obtained by distilling off thesolvent under reduced pressure was suspended in N,N-dimethylformamide(10 ml), followed by the addition of 4-(4-pyridyl)benzoic acid (420 mg)obtained in Referential Example 2 and N,N-dimethyl-4-aminopyridine (309mg). Under ice cooling, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (405 mg) was added and the resulting mixture was stirredat room temperature for 68 hours. After concentration, the residue waspurified by chromatography on a silica gel column(dichloromethane:methanol=70:1). The colorless solid so obtained wasrecrystallized from a mixed solvent of ethyl acetate and hexane,followed by recrystallization from ethyl acetate to obtain colorlessneedle crystals (185 mg). To the filtrate, on the other hand, saturatedhydrochloric acid ethanol (4 ml) was added. After concentration, theresidue was recrystallized from methanol—ethyl acetate, whereby thetitle compound (200 mg) was obtained as colorless needle crystals.

[4227]¹H-NMR (DMSO-d₆) δ: 3.17 (2H, br s), 3.23 (2H, br s), 3.48 (2H, brs), 3.77 (2H, br s), 7.36 (1H, d, J=15.3 Hz), 7.44 (1H, d, J=15.3 Hz),7.53 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz),8.06 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=6.6 Hz), 8.95 (2H, d, J=6.6 Hz).

[4228] MS (FAB) m/z: 468 [(M+H)⁺, Cl³⁵], 470 [(M+H)⁺, Cl³⁷].

[4229] Elementary analysis for C₂₄H₂₂ClN₃O₃S.HCl.0.2H₂O.0.22CH₃CO₂CH₂CH₃

[4230] Calculated: C, 56.66; H, 4.81; Cl, 13.44; N, 7.97; S, 6.08.

[4231] Found: C, 56.68; H, 4.79; Cl, 13.43; N, 8.04; S, 6.14.

Example A-254-[4-[[4-[(E)-4-Chlorostyrylsulfonyl]piperazin-1-yl]carbonyl]phenyl]-1-methylpyridiniumIodide

[4232] In the same manner as in Example A-12, a reaction was conductedusing1-[(E)-4-chlorostyrylsulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine,which had been obtained in Example A-24, as a starting material, wherebythe title compound was obtained.

[4233]¹H-NMR (DMSO-d₆) δ: 3.04-3.87 (8H, br), 4.35 (3H, s), 7.35 (1H, d,J=15.6 Hz), 7.44 (1H, d, J=15.6 Hz), 7.53 (2H, d, J=8.3 Hz), 7.67 (2H,d, J=8.3 Hz), 7.82 (2H, d, J=8.8 Hz), 8.13 (2H, d, J=8.3 Hz), 8.53 (2H,d, J=6.8 Hz), 9.05 (2H, d, J=7.3 Hz).

[4234] Elementary analysis for C₂₅H₂₅ClIN₃O₃S.0.5H₂O

[4235] Calculated: C, 48.52; H, 4.23; N, 6.79.

[4236] Found: C, 48.68; H, 4.13; N, 6.41.

Example A-263-[4-[[4-[(E)-4-Chlorostyrylsulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4237] After the protective group was removed by the reaction as inExample A-7, the reaction with (E)-4-chlorostyrylsulfonyl chloride(WO96/10022) was effected in the same manner as in Example A-23, wherebythe title compound was obtained.

[4238]¹H-NMR (CDCl₃) δ: 3.26 (4H, br), 3.52-4.00 (4H, br), 6.64 (1H, d,J=15.6 Hz), 7.45-7.52 (7H, m), 7.52 (2H, d, J=2.0 Hz), 7.57 (2H, d,J=2.0 Hz), 8.22 (1H, dt, J=6.3, 1.6 Hz), 8.44 (1H, t, J=1.6 Hz).

[4239] MS (FAB) m/z: 484 [(M+H)⁺, Cl³⁵], 486 [(M+H)⁺, Cl³⁷].

[4240] Elementary analysis for C₂₄H₂₂ClN₃O₃S.0.5H₂O

[4241] Calculated: C, 58.47; H, 4.70; Cl, 7.19; N, 8.52; S, 6.50.

[4242] Found: C, 58.49; H, 4.66; Cl, 7.40; N, 8.54; S, 6.56.

Example A-271-[(E)-4-Chlorostyrylsulfonyl]-4-[4-(pyridin-3-yl)benzoyl]piperazineHydrochloride

[4243] In the same manner as in Example A-17 except for the use, asstarting materials, of 4-(3-pyridyl)benzoic acid hydrochloride and1-[(E)-4-chlorostyrylsulfonyl]piperazine hydrochloride, a reaction wasconducted, whereby the title compound was obtained.

[4244]¹H-NMR (DMSO-d₆) δ: 3.08-3.29 (4H, br), 3.42-3.85 (4H, br), 7.35(1H, d, J=15.6 Hz), 7.43 (1H, d, J=15.6 Hz), 7.52 (2H, d, J=8.3 Hz),7.59 (2H, d, J=8.3 Hz), 7.80-7.93 (5H, m), 8.54 (1H, d, J=6.8 Hz), 8.78(1H, d, J=4.5 Hz), 9.13 (1H, d, J=2.0 Hz).

[4245] MS (FAB) m/z: 468 [(M+H)⁺, Cl³⁵], 470 [(M+H)⁺, Cl³⁷].

[4246] Elementary analysis for C₂₄H₂₂ClN₃O₃S.HCl.1.3H₂O

[4247] Calculated: C, 54.61; H, 4.89; N, 7.96; Cl, 13.43; S, 6.07.

[4248] Found: C, 54.82; H, 4.80; N, 7.91; Cl, 13.14; S, 6.14.

Example A-283-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-1-methylpyridiniumIodide

[4249] In the same manner as in Example A-12, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-3-yl)benzoyl]piperazine,which had been obtained in Example A-5, as a starting material, wherebythe title compound was obtained.

[4250]¹H-NMR (DMSO-d₆) δ: 2.50-3.80 (8H, m), 4.44 (3H, s), 7.57 (2H, d,J=8.3 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.84 (1H, dd, J=8.8, 1.5 Hz),7.94 (2H, d, J=8.3 Hz), 8.10-8.30 (4H, m), 8.51 (1H, s), 8.90 (1H, d,J=7.8 Hz), 9.01 (1H, d, J=5.9 Hz), 9.45 (1H, s).

[4251] MS (FAB) m/z: 506 [(M+H)⁺, Cl³⁵], 508 [(M+H)⁺, Cl³⁷].

Example A-291-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[2-hydroxy-4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4252] In the same manner as in Example A-4, a reaction was conductedusing 2-(hydroxy-4-(4-pyridyl)benzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4253]¹H-NMR (DMSO-d₆) δ: 2.90-3.40 (8H, m), 7.25-7.40 (3H, m),7.70-7.80 (1H, m), 7.80-7.90 (1H, m), 8.15-8.25 (3H, m), 8.25-8.35 (2H,m), 8.50-8.60 (1H, m), 8.91 (2H, d, J=6.4 Hz), 10.41 (1H, br s).

[4254] MS (FAB) m/z: 535 [(M+H)⁺, Cl³⁵], 537 [(M+H)⁺, Cl³⁷].

[4255] Elementary analysis for C₂₆H₂₂ClN₃O₄S.1.1HCl.1.7H₂O

[4256] Calculated: C, 53.96; H, 4.62; N, 7.26; Cl, 12.86; S, 5.54.

[4257] Found: C, 53.62; H, 4.58; N, 7.34; Cl, 13.10; S, 5.94.

Example A-301-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-methoxy-4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4258] In the same manner as in Example A-4, a reaction was conductedusing 3-methoxy-4-(4-pyridyl)benzoic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4259]¹H-NMR (DMSO-d₆) δ: 3.00-4.00 (8H, m), 3.81 (3H, s), 7.08 (1H, d,J=8.8 Hz), 7.17 (1H, s), 7.55 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.8,2.0 Hz), 7.83 (1H, d, J=8.3 Hz), 8.04 (2H, d, J=6.3 Hz), 8.19 (1H, d,J=8.8 Hz), 8.25-8.30 (2H, m), 8.52 (1H, s), 8.85 (2H, d, J=6.3 Hz).

[4260] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁷].

[4261] Elementary analysis for C₂₇H₂₄ClN₃O₄S.0.8HCl.1.7H₂O

[4262] Calculated: C, 55.74; H, 4.89; N, 7.22; Cl, 10.97; S, 5.51.

[4263] Found: C, 55.59; H, 4.90; N, 7.23; Cl, 10.90; S, 5.52.

Example A-311-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-hydroxy-4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4264] In dichloromethane (1 ml), boron tribromide (115 μl) wasdissolved, followed by the dropwise addition of a solution of1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[3-methoxy-4-(pyridin-4-yl)benzoyl]piperazine,which had been obtained in Example A-30, in dichloromethane(dichloromethane: 4 ml) at an external temperature of about −78° C.While heating gradually to room temperature, the resulting mixture wasstirred for 23 hours. After dichloromethane and water were added to thereaction mixture and the resulting mixture was stirred for a while,sodium bicarbonate was added to make alkaline the reaction mixture,which was separated into an organic layer and a water layer. From thewater layer, another organic layer was extracted with dichloromethane.These organic layers were combined together, washed with saturatedaqueous NaCl solution and then dried over anhydrous sodium sulfate. Theresidue obtained by distilling off the solvent under reduced pressurewas purified by chromatography on a silica gel column(dichloromethane˜3% methanol—dichloromethane). The crudely purifiedproduct so obtained was dissolved in tetrahydrofuran. Solution ofhydrochloride in ethanol was added to the resulting solution to solidifythe same. The resulting solid was collected by filtration and thendissolved in a mixed solvent of water and methanol. After the removal ofthe insoluble matter by filtration, the filtrate was distilled underreduced pressure, whereby the title compound (36 mg, 30%) was obtained.

[4265]¹H-NMR (DMSO-d₆) δ: 3.00-3.80 (8H, m), 6.85-6.95 (1H, m), 7.01(1H, d, J=1.4 Hz), 7.49 (1H, d, J=8.8 Hz), 7.72 (1H, dd, J=8.8, 2.0 Hz),7.81 (1H, dd, J=8.5, 1.7 Hz), 7.94 (2H, d, J=6.4 Hz), 8.19 (1H, d, J=8.8Hz), 8.25-8.30 (2H, m), 8.51 (1H, s), 8.75 (2H, d, J=5.9 Hz), 10.67 (1H,s).

[4266] MS (FAB) m/z: 508 [(M+H)⁺, Cl³⁵], 510 [(M+H)⁺, Cl³⁷].

Example A-321-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4267] In the same manner as in Example A-7, a reaction was effectedusing4-tert-butoxycarbonyl-1-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazineas a starting material and the protective group was removed. The residuewas then reacted with 4-(4-pyridyl)benzoic acid hydrochloride as inExample A-4, whereby the title compound was obtained.

[4268]¹H-NMR (CDCl₃) δ: 0.80-1.10 (3H, m), 3.00-4.00 (8H, m), 4.60-4.80(1H, m), 7.42 (2H, d, J=7.8 Hz), 7.47 (2H, d, J=5.9 Hz), 7.50-7.60 (1H,m), 7.64 (2H, d, J=8.3 Hz), 7.70-7.80 (1H, m), 7.85-7.95 (3H, m), 8.33(1H, s), 8.69 (2H, s).

[4269] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁷].

[4270] Elementary analysis for C₂₉H₂₆ClN₃O₅S.0.3H₂O

[4271] Calculated: C, 60.78; H, 4.70; N, 7.33; Cl, 6.80; S, 5.60.

[4272] Found: C, 60.84; H, 4.84; N, 6.98; Cl, 7.03; S, 5.70.

Example A-331-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine-2-carboxylicAcid

[4273] In the same manner as in Example A-3, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-4-[4-(pyridin-4-yl)benzoyl]piperazineas a starting material.

[4274]¹H-NMR (DMSO-d₆) δ: 2.70-5.00 (7H, m), 7.40-7.50 (2H, m),7.65-7.75 (2H, m), 7.85-8.25 (8H, m), 8.50-8.60 (2H, m), 8.80-8.95 (2H,m).

[4275] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

[4276] Elementary analysis for C₂₇H₂₂ClN₃O₅S.0.3HCl.H₂O

[4277] Calculated: C, 57.40; H, 4.34; N, 7.44; Cl, 8.16; S, 5.68.

[4278] Found: C, 57.16; H, 4.35; N, 7.36; Cl, 7.92; S, 6.08.

Example A-344-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-3-yl)benzoyl]piperazine

[4279] In the same manner as in Example A-2, a reaction was effected,whereby the title compound was obtained.

[4280]¹H-NMR (CDCl₃) δ: 1.15-1.30 (3H, m), 2.60-4.60 (8H, m), 5.33 (1H,br), 7.40-7.55 (3H, m), 7.70-7.85 (4H, m), 8.05-8.10 (1H, m), 8.19 (1H,d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.50-8.65 (2H, m), 8.91 (1H, s).

[4281] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁷].

[4282] Elementary analysis for C₂₉H₂₆ClN₃O₅S.0.1HCl.0.5H₂O

[4283] Calculated: C, 60.40; H, 4.74; N, 7.29; Cl, 6.76; S, 5.56.

[4284] Found: C, 60.67; H, 4.61; N, 7.30; Cl, 6.89; S, 5.51.

Example A-352-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-3-yl)benzoyl]piperazineHydrochloride

[4285] In the same manner as in Example A-3, with4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-3-yl)benzoyl]piperazine (426mg) as a starting material, a crude product was obtained by thehydrolysis of the ester, followed by suspension in N,N-dimethylformamide(35 ml). Under ice cooling, di-tert-butyl dicarbonate (646 mg), pyridine(370 μl) and ammonium bicarbonate (196 mg) were added to the resultingsuspension. The resulting mixture was stirred at room temperature for 19hours. The residue obtained by distilling off the solvent under reducedpressure was purified by chromatography on a silica gel column (4%methanol—dichloromethane) and the eluate was dissolved intetrahydrofuran. Solution of hydrochloride in ethanol was added to theresulting solution to solidify the same. The resulting solid wascollected by filtration and dissolved in a mixed solvent of water andmethanol. The insoluble matter was filtered off and the filtrate wasdistilled under reduced pressure, whereby the title compound (302 mg,65%) was obtained.

[4286]¹H-NMR (DMSO-d₆) δ: 2.30-4.50 (6H, m), 5.08 (1H, br), 7.40-7.60(2H, m), 7.65-7.85 (3H, m), 7.92 (2H, d, J=7.8 Hz), 8.00-8.10 (1H, m),8.20 (2H, d, J=8.8 Hz), 8.25-8.35 (2H, m), 8.49 (1H, s), 8.80 (1H, d,J=7.8 Hz), 8.88 (1H, d, J=5.4 Hz), 9.25 (1H, s).

[4287] MS (FAB) m/z: 535 [(M+H)⁺, Cl³⁵], 537 [(M+H)⁺, Cl³⁷].

[4288] Elementary analysis for C₂₇H₂₃ClN₄O₄S.1.1HCl.1.7H₂O

[4289] Calculated: C, 53.54; H, 4.58; N, 9.25; Cl, 12.29; S, 5.29.

[4290] Found: C, 53.36; H, 4.71; N, 9.07; Cl, 12.17; S, 5.50.

Example A-362-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4291] In the same manner as in Example A-35, the title compound wasobtained using4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-4-yl)benzoyl]piperazineas a starting material.

[4292]¹H-NMR (DMSO-d₆) δ: 2.30-2.70 (2H, m), 3.20-3.80 (2H, m),4.10-4.50 (2H, m), 5.07 (1H, br s), 7.40-7.55 (2H, m), 7.60-7.65 (1H,m), 7.67 (1H, s), 7.72 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.8, 2.4Hz), 8.04 (2H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.25-8.35 (4H, m),8.49 (1H, s), 8.95 (2H, d, J=5.4 Hz)

[4293] MS (FAB) m/z: 535 [(M+H)⁺, Cl³⁵], 537 [(M+H)⁺, Cl³⁷].

[4294] Elementary analysis for C₂₇H₂₃ClN₄O₄S.HCl.1.8H₂O

[4295] Calculated: C, 53.70; H, 4.61; N, 9.28; Cl, 11.74; S, 5.31.

[4296] Found: C, 53.87; H, 4.40; N, 8.89; Cl, 11.81; S, 5.23.

Example A-374-[4-[[2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4297] In the same manner as in Example A-6, a reaction was conductedusing2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-pyridin-4-yl)benzoyl]piperazineas a starting material, whereby the title compound was obtained.

[4298]¹H-NMR (DMSO-d₆) δ: 2.30-4.50 (6H, m), 5.04 (1H, br), 7.30-7.90(10H, m), 8.10-8.30 (5H, m), 8.48 (1H, s).

[4299] MS (FAB) m/z: 551 [(M+H)⁺, Cl³⁵], 553 [(M+H)⁺, Cl³⁷].

[4300] Elementary analysis for C₂₇H₂₃ClN₄O₅S.0.8H₂O

[4301] Calculated: C, 57.35; H, 4.39; N, 9.91; Cl, 6.27; S, 5.67.

[4302] Found: C, 57.64; H, 4.50; N, 9.48; Cl, 6.37; S, 5.71.

Example A-384-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4303] In the same manner as in Example A-37, a reaction was conducted,whereby the title compound was obtained.

[4304]¹H-NMR (CDCl₃) δ: 1.30-1.40 (3H, m), 2.30-4.70 (8H, m), 5.47 (1H,br s), 7.40-7.80 (8H, m), 7.92 (1H, s), 7.94 (2H, s), 8.26 (2H, d, J=6.8Hz), 8.48 (1H, s).

[4305] MS (FAB) m/z: 580 [(M+H)⁺, Cl³⁵], 582 [(M+H)⁺, Cl³⁷].

[4306] Elementary analysis for C₂₉H₂₆ClN₃O₆S.1.3H₂O

[4307] Calculated: C, 57.72; H, 4.78; N, 6.96; Cl, 5.87; S, 5.31.

[4308] Found: C, 57.99; H, 4.75; N, 6.56; Cl, 5.98; S, 5.43.

Example A-394-[4-[[2-Carboxy-4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4309] In the same manner as in Example A-3, the title compound wasobtained.

[4310]¹H-NMR (CDCl₃) δ: 2.30-4.50 (6H, m), 5.22 (1H, br s), 7.35-7.50(2H, m), 7.70-7.90 (6H, m), 8.19 (1H, d, J=8.8 Hz), 8.25-8.30 (4H, m),8.53 (1H, s), 13.42 (1H, br).

[4311] Elementary analysis for C₂₇H₂₂ClN₃O₆S.0.2HCl.1.7H₂O

[4312] Calculated: C, 54.97; H, 4.37; N, 7.12; Cl, 7.21; S, 5.44.

[4313] Found: C, 55.07; H, 4.40; N, 6.82; Cl, 7.16; S, 5.47.

Example A-402-Carbamoyl-4-[(E)-4-chlorostyrylsulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazinehydrochloride, and2-Carbamoyl-4-[[2-(4-chlorophenyl)-2-ethoxyethyl]sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4314] In the same manner as in Example A-35, a reaction was conducted,whereby the title compounds were obtained.2-Carbamoyl-4-[(E)-4-chlorostyrylsulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4315]¹H-NMR (CD₃OD) δ: 2.80-4.80 (6H, m), 5.32 (1H, br), 7.04 (1H, d,J=15.6 Hz), 7.40-7.50 (3H, m), 7.60-7.80 (4H, m), 7.95-8.05 (2H, m),8.20 (2H, br), 8.81 (2H, br).

[4316] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

[4317] Elementary analysis for C₂₅H₂₃ClN₄O₄S.0.9HCl.1.8H₂O

[4318] Calculated: C, 52.11; H, 4.81; N, 9.72; Cl, 11.69.

[4319] Found: C, 52.28; H, 4.83; N, 9.44; Cl, 11.51.

[4320]2-Carbamoyl-4-[[2-(4-chlorophenyl)-2-ethoxyethyl]sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4321]¹H-NMR (CD₃OD) δ: 1.10-1.20 (3H, m), 2.95-4.70 (6H, m), 5.34 (1H,br), 7.38 (4H, s), 7.65-7.85 (2H, m), 8.05-8.15 (2H, m), 8.40-8.50 (2H,m), 8.91 (2H, d, J=5.9 Hz).

[4322] MS (FAB) m/z: 557 [(M+H)⁺, Cl³⁵], 559 [(M+H)⁺, Cl³⁷].

[4323] Elementary analysis for C₂₇H₂₉ClN₄O₅S.HCl.2.5H₂O

[4324] Calculated: C, 50.78; H, 5.52; N, 8.77; Cl, 11.10; S, 5.02.

[4325] Found: C, 50.61; H, 5.38; N, 8.68; Cl, 11.27; S, 5.07.

Example A-411-[trans-4-(Aminomethyl)cyclohexylmethyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4326] In the same manner as in Example A-7, a reaction was conducted,whereby the title compound was obtained.

[4327]¹H-NMR (DMSO-d₆) δ: 0.80-1.00 (4H, m), 1.48 (1H, m), 1.60-1.90(5H, m), 2.60 (2H, m), 2.90-3.10 (4H, m), 3.14 (2H, m), 3.52 (2H, m),3.77 (2H, m), 7.75 (1H, dd, J=8.8, 2.0 Hz), 7.85 (1H, d, J=8.8 Hz), 7.99(3H, br), 8.21 (1H, d, J=8.8 Hz), 8.30-8.40 (2H, m), 8.56 (1H, s), 10.46(1H, br).

[4328] MS (FAB) m/z: 436 [(M+H)⁺, Cl³⁵], 438 [(M+H)⁺, Cl³⁷].

[4329] Elementary analysis for C₂₂H₃₀ClN₃O₂S.2HCl.¾H₂O

[4330] Calculated: C, 50.58; H, 6.46; N, 8.04; Cl, 20.36; S, 6.14.

[4331] Found: C, 50.74; H, 6.48; N, 7.76; Cl, 20.09; S, 6.19.

Example A-421-[trans-4(Aminomethyl)cyclohexylcarbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4332] In the same manner as in Example A-7, the title compound wasobtained using1-[trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4333]¹H-NMR (DMSO-d₆) δ: 0.90-1.00 (2H, m), 1.20-1.40 (2H, m), 1.48(1H, m), 1.50-1.70 (2H, m), 1.70-1.90 (2H, m), 2.44 (1H, m), 2.59 (2H,m), 2.96 (4H, m), 3.55 (4H, m), 7.72 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H,d, J=8.3 Hz), 7.90 (3H, br), 8.16 (1H, d, J=8.8 Hz), 8.20-8.30 (2H, m),8.49 (1H, s).

[4334] MS (FAB) m/z: 450 [(M+H)⁺, Cl³⁵], 452 [(M+H)⁺, Cl³⁷].

[4335] Elementary analysis for C₂₂H₂₈ClN₃O₃S.0.9HCl.1.5H₂O

[4336] Calculated: C, 51.83; H, 6.31; N, 8.24; Cl, 13.21; S, 6.29.

[4337] Found: C, 51.63; H, 6.22; N, 7.97; Cl, 13.32; S, 6.17.

Example A-431-[N-[trans-4-(Aminomethyl)cyclohexylcarbonyl]glycyl]]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4338] In the same manner as in Example A-7, a reaction was conductedusing1-[N-[trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexylcarbonyl]glycyl]]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material, whereby the title compound was obtained.

[4339]¹H-NMR (DMSO-d₆) δ: 0.80-1.00 (2H, m), 1.20-1.40 (2H, m), 1.50(1H, m), 1.60-1.80 (4H, m), 2.10 (1H, m), 2.62 (2H, m), 2.90-3.10 (4H,m), 3.40-3.60 (4H, m), 3.83 (2H, d, J=5.4 Hz), 7.70-7.90 (3H, m), 7.93(3H, br), 8.17 (1H, d, J=8.3 Hz), 8.20-8.30 (2H, m), 8.49 (1H, s).

[4340] MS (FAB) m/z: 507 [(M+H)⁺, Cl³⁵], 509 [(M+H)⁺, Cl³⁷].

[4341] Elementary analysis for C₂₄H₃₁ClN₄O₄S.HCl

[4342] Calculated: C, 53.04; H, 5.93; N, 10.31; Cl, 13.05; S, 5.90.

[4343] Found: C, 52.90; H, 5.98; N, 10.29; Cl, 12.98; S, 5.91.

Example A-441-[trans-4-(Aminomethyl)cyclohexylcarbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazineHydrochloride

[4344] In the same manner as in Example A-7, the title compound wasobtained using1-[trans-4-(N-tert-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazineas a starting material.

[4345]¹H-NMR (DMSO-d₆) δ: 0.90-1.10 (2H, m), 1.30-1.50 (2H, m),1.50-1.90 (7H, m), 2.40-2.80 (3H, m), 3.20-3.70 (8H, m), 7.60-7.70 (1H,m), 7.80-8.00 (4H, m), 8.10-8.20 (1H, m), 8.20-8.30 (2H, m), 8.52 and8.53 (1H, each s).

[4346] MS (FAB) m/z: 464 [(M+H)⁺, Cl³⁵], 466 [(M+H)⁺, Cl³⁷].

[4347] Elementary analysis for C₂₃H₃₀ClN₃O₃S.HCl

[4348] Calculated: C, 55.20; H, 6.24; N, 8.40; Cl, 14.17; S, 6.41.

[4349] Found: C, 55.42; H, 6.18; N, 8.26; Cl, 14.11; S, 6.53.

Example A-451-[4-(Aminomethyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4350] In the same manner as in Example A-7, the title compound wasobtained using1-[4-(N-tert-butoxycarbonylaminomethyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4351]¹H-NMR (DMSO-d₆) δ: 3.00-3.20 (4H, br), 3.30-3.80 (4H, br), 4.03(2H, s), 7.37 (2H, d, J=7.3 Hz), 7.50 (2H, d, J=7.3 Hz) 7.72 (1H, d,J=8.8 Hz), 7.82 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.20-8.40(2H, m), 8.43 (3H, br), 8.49 (1H, s).

[4352] MS (FAB) m/z: 444 [(M+H)⁺, Cl³⁵], 446 [(M+H)⁺, Cl³⁷].

[4353] Elementary analysis for C₂₂H₂₂ClN₃O₃S.HCl.H₂O

[4354] Calculated: C, 53.02; H, 5.06; N, 8.43; Cl, 14.23; S, 6.43.

[4355] Found: C, 53.06; H, 5.30; N, 8.32; Cl, 14.20; S, 6.44.

Example A-461-[3-(Aminomethyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4356] In the same manner as in Example A-3, the ester was hydrolyzedusing methyl 3-(N-tert-butoxycarbonylaminomethyl)benzoate as a startingmaterial. Reaction was then effected as in Example A-4 or A-7, wherebythe title compound was obtained.

[4357]¹H-NMR (DMSO-d₆) δ: 3.07 (4H, br), 3.20-3.80 (4H, br), 4.00 (2H,s), 7.30-7.60 (4H, m), 7.73 (1H, d, J=8.8 Hz), 7.83 (1H, d, J=8.8 Hz),8.10-8.60 (7H, m).

[4358] MS (FAB) m/z: 444 [(M+H)⁺, Cl³⁵], 446 [(M+H)⁺, Cl³⁷].

[4359] Elementary analysis for C₂₂H₂₂ClN₃O₃S.HCl.¼H₂O

[4360] Calculated: C, 54.49; H, 4.88; N, 8.67; Cl, 14.62; S, 6.61.

[4361] Found: C, 54.64; H, 4.95; N, 8.52; Cl, 14.59; S, 6.70.

Example 471-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-[N-(1-pyrrolin-2-yl)aminomethyl]benzoyl]piperazineHydrochloride

[4362] In dimethylformamide (2 ml), 2-methoxy-1-pyrroline (35 mg) wasdissolved, followed by the addition of1-[3-(aminomethyl)benzoyl]-4-[(6-chloronaphthalen-2-ylsulfonyl]piperazinehydrochloride (0.10 g) and triethylamine (44 μl). The resulting mixturewas stirred at room temperature for 3 days. After the reaction mixturewas concentrated under reduced pressure, the concentrate was dilutedwith methanol, followed by the addition of 1N hydrochloric acid. Thesolvent was then distilled off under reduced pressure. The residue waspurified by gel permeation chromatography (“Sephadex LH-20”, Ø 15×300mm, methanol), followed by solidification in a mixed solvent of methanoland ether, whereby a colorless solid (0.11 g, 91%) was obtained.

[4363]¹H-NMR (DMSO-d₆) δ: 2.04 (2H, m), 2.81 (2H, t, J=7.8 Hz), 3.18(4H, br), 3.20-3.80 (5H, m), 4.10 (1H, br), 4.51 (2H, d, J=5.9 Hz),7.30-7.50 (4H, m), 7.72 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, d, J=8.8 Hz),8.18 (1H, d, J=8.8 Hz), 8.20-8.30 (2H, m), 8.50 (1H, s), 10.01 (1H, t,J=5.9 Hz), 10.06 (1H, s).

[4364] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

[4365] Elementary analysis for C₂₆H₂₇ClN₄O₃S.HCl.CH₃OH.⅘H₂

[4366] Calculated: C, 54.60; H, 5.70; N, 9.43; Cl, 11.94; S, 5.40.

[4367] Found: C, 54.84; H, 5.47; N, 9.13; Cl, 11.86; S, 5.48.

Example A-481-[4-(2-Aminoethyl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4368] In the same manner as in Example A-7, the title compound wasobtained using1-[4-(2-(tert-butoxycarbonylamino)ethyl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4369]¹H-NMR (DMSO-d₆) δ: 2.90-3.20 (8H, m), 3.40-3.90 (4H, br), 7.28(4H, s), 7.72 (1H, dd, J=8.8, 2.4 Hz), 7.81 (1H, dd, J=8.8, 2.0 Hz),8.02 (3H, br), 8.17 (1H, d, J=8.3 Hz), 8.20-8.30 (2H, m), 8.49 (1H, s).

[4370] MS (FAB) m/z: 458 [(M+H)⁺, Cl³⁵], 460 [(M+H)⁺, Cl³⁷].

[4371] Elementary analysis for C₂₃H₂₄ClN₃O₃S.HCl.½CH₃OH.½H₂O

[4372] Calculated: C, 54.34; H, 5.43; N, 8.09; Cl, 13.65; S, 6.17.

[4373] Found: C, 54.43; H, 5.26; N, 7.92; Cl, 13.58; S, 6.24.

Example A-491-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[4-[[(3S)-pyrrolidin-3-yl]oxy]benzoyl]piperazineHydrochloride

[4374] In the same manner as in Example A-7, the title compound wasobtained using1-[4-[[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4375]¹H-NMR (DMSO-d₆) δ: 2.05-2.25 (2H, m), 3.00-3.10 (4H, m),3.20-3.70 (8H, m), 5.16 (1H, br s), 6.95 (2H, d, J=8.8 Hz), 7.31 (2H, d,J=8.3 Hz), 7.70-7.75 (1H, m), 7.82 (1H, dd, J=8.5, 1.7 Hz), 8.18 (2H, d,J=8.8 Hz), 8.20-8.30 (2H, m), 8.50 (1H, s).

[4376] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

Example A-501-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[3-[[(3S)-pyrrolidin-3-yl]oxy]benzoyl]piperazineHydrochloride

[4377] In the same manner as in Example 7, the title compound wasobtained using1-[3-[[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4378]¹H-NMR (DMSO-d₆) δ: 2.00-2.20 (2H, m), 2.95-3.15 (4H, m),3.20-3.80 (8H, m), 5.11 (1H, br s), 6.90-6.95 (3H, m), 7.00-7.05 (1H,m), 7.30-7.35 (1H, m), 7.72 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, dd,J=8.5, 1.7 Hz), 8.18 (2H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.50 (1H, s).

[4379] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

[4380] Elementary analysis for C₂₅H₂₆ClN₃O₄S.HCl.H₂O

[4381] Calculated: C, 54.15; H, 5.27; N, 7.58; Cl, 12.79; S, 5.78.

[4382] Found: C, 53.84; H, 5.19; N, 7.33; Cl, 12.72; S, 5.86.

Example A-511-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[4-[[(3R)-pyrrolidin-3-yl]oxy]benzoyl]piperazineHydrochloride

[4383] In the same manner as in Example A-7, the title compound wasobtained using1-[4-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4384]¹H-NMR (DMSO-d₆) δ: 2.05-2.25 (2H, m), 3.00-3.10 (4H, m),3.20-3.70 (8H, m), 5.16 (1H, br s), 6.96 (2H, d, J=8.8 Hz), 7.31 (2H, d,J=8.8 Hz), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 1.5 Hz),8.18 (1H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.50 (1H, s).

[4385] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

[4386] Elementary analysis for C₂₅H₂₆ClN₃O₄S.1.2HCl.0.8H₂O

[4387] Calculated: C, 53.80; H, 5.20; N, 7.53; Cl, 13.97; S, 5.74.

[4388] Found: C, 53.84; H, 5.05; N, 7.51; Cl, 13.79; S, 5.74.

Example A-521-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[3-[[(3R)-pyrrolidin-3-yl]oxy]benzoyl]piperazineHydrochloride

[4389] In the same manner as in Example A-7, the title compound wasobtained using1-[3-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]oxy]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4390]¹H-NMR (DMSO-d₆): δ: 2.00-2.20 (2H, m), 2.95-3.15 (4H, m),3.20-3.80 (8H, m), 5.11 (1H, br s), 6.90-6.95 (2H, m), 7.00-7.05 (1H,m), 7.30-7.35 (1H, m), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd,J=8.8, 1.5 Hz), 8.18 (2H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.50 (1H, s).

[4391] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

[4392] Elementary analysis for C₂₅H₂₆ClN₃O₄S.HCl.H₂O

[4393] Calculated: C, 54.15; H, 5.27; N, 7.58; Cl, 12.79; S, 5.78.

[4394] Found: C, 53.91; H, 5.14; N, 7.37; Cl, 12.62; S, 5.67.

Example A-531-[4-(2-Aminopyrimidin-5-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl]sulfonyl]piperazineHydrochloride

[4395] In the same manner as in Example A-4, a reaction-was conductedusing 4-(2-amino-5-pyrimidyl)benzoic acid and1-[(6-chloronaphthalen-2-yl]sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4396]¹H-NMR (DMSO-d₆) δ: 3.06 (4H, br), 3.56 and (each 2H, br),4.70-5.45 (3H, br), 7.40 (2H, d, J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.73(1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz),8.27 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.50 (1H, s), 8.72 (1H, s).

[4397] MS (FAB) m/z: 508 [(M+H)⁺, Cl³⁵], 510 [(M+H)⁺, Cl³⁷].

[4398] Elementary analysis for C₂₅H₂₂ClN₅O₃S.1.1HCl.0.7H₂O

[4399] Calculated: C, 53.55; H, 4.40; Cl, 13.28; N, 12.49; S, 5.72.

[4400] Found: C, 53.59; H, 4.58; Cl, 13.02; N, 12.58; S,

Example A-541-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[(piperidin-4-yl)acetyl]piperazineHydrochloride

[4401] In the same manner as in Example A-7, the title compound wasobtained using1-[(1-tert-butoxycarbonylpiperidin-4-yl)acetyl]-4-[(6-chloronaphthalen-2-yl]sulfonyl]piperazineas a starting material.

[4402]¹H-NMR (DMSO-d₆) δ: 1.25 (2H, m), 1.71 (2H, m), 1.87 (1H, m), 2.20(2H, d, J=6.8 Hz), 2.78 (2H, br), 2.96 (4H, br s), 3.14 (2H, m), 3.52(4H, br s), 4.02 (2H, br), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, d,J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.28 (1H, d, J=8.8 Hz), 8.26 (1H, s),8.50 (1H, s), 8.54 (1H, br), 8.75 (1H, br).

[4403] MS (FAB) m/z: 436 [(M+H)⁺, Cl³⁵], 438 [(M+H)⁺, Cl³⁷].

[4404] Elementary analysis for C₂₁H₂₆ClN₃O₃S.1.1HCl.1.1H₂O

[4405] Calculated: C, 50.86; H, 5.96; Cl, 15.01; N, 8.47; S, 6.47.

[4406] Found: C, 51.07; H, 5.74; Cl, 14.75; N, 8.36; S, 6.50.

Example A-551-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[3-(piperidin-4-yl)propionyl]piperazineHydrochloride

[4407] In the same manner as in Example A-7, the title compound wasobtained using1-[3-(1-tert-butoxycarbonylpiperidin-4-yl)propionyl]-4-[(6-chloronaphthalen-2-yl]sulfonyl]piperazineas a starting material.

[4408]¹H-NMR (CD₃OD) δ: 1.29 (2H, m), 1.50 (1H, m), 1.51 (2H, m), 1.89(2H, m), 2.36 (2H, m), 2.88 (2H, m), 3.08 (4H, m), 3.64 (4H, m), 4.04(2H, br), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz),8.05 (1H, d, J=8.8 Hz), 8.06 (1H, s), 8.09 (1H, d, J=8.8 Hz), 8.42 (1H,s).

[4409] MS (FAB) m/z: 450 [(M+H)⁺, Cl³⁵], 452 [(M+H)⁺, Cl³⁷].

[4410] Elementary analysis for C₂₂H₂₈ClN₃O₃S.1.8HCl.0.9H₂O

[4411] Calculated: C, 49.68; H, 5.99; Cl, 18.66; N, 7.90; S, 6.03.

[4412] Found: C, 49.45; H, 5.70; Cl, 18.63; N, 7.72; S, 6.04.

Example A-561-[(6-Chloronaphthalen-2-yl]sulfonyl]-4[(E)-3-(pyridin-3-yl)propenoyl]piperazineHydrochloride

[4413] In the same manner as in Example A-4, the title compound wasobtained using (E)-3-(3-pyridyl)acrylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[4414]¹H-NMR (DMSO-d₆) δ: 3.03 (4H, m), 3.69 (2H, br), 3.85 (2H, br),7.51 (2H, s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0Hz), 7.89 (1H, dd, J=7.8, 5.4 Hz), 8.16 (1H, d, J=8.8 Hz), 8.22 (1H, d,J=2.0 Hz), 8.26 (1H, d, J=8.8 Hz), 8.51 (1H, s), 8.67 (1H, d, J=7.8 Hz),8.77 (1H, d, J=5.4 Hz), 9.13 (1H, s).

[4415] MS (FAB) m/z: 442 [(M+H)⁺, Cl³⁵], 444 [(M+H)⁺, Cl³⁷].

[4416] Elementary analysis for C₂₂H₂₀ClN₃O₃S.HCl.¼H₂O

[4417] Calculated: C, 54.72; H, 4.49; N, 8.70; Cl, 14.68; S, 6.64.

[4418] Found: C, 54.81; H, 4.43; N, 8.54; Cl, 14.68; S, 6.74.

Example A-571-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[(E)-3-(pyridin-4-yl)propenoyl]piperazineHydrochloride

[4419] In the same manner as in Example A-4, the title compound wasobtained using (E)-3-(4-pyridyl)acrylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[4420]¹H-NMR (DMSO-d₆) δ: 3.03 (4H, m), 3.68 (2H, br), 3.82 (2H, br),5.76 (1H, s), 7.48 (1H, d, J=15.1 Hz), 7.65 (1H, d, J=15.1 Hz), 7.72(1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.11 (2H, br s),8.16 (1H, d, J=8.8 Hz), 8.24 (1H, s), 8.27 (1H, d, J=8.8 Hz), 8.52 (1H,s), 8.82 (2H, d, J=5.9 Hz).

[4421] MS (FAB) m/z: 442 [(M+H)⁺, Cl³⁵], 444 [(M+H)⁺, Cl³⁷].

[4422] Elementary analysis for C₂₂H₂₀ClN₃O₃S.HCl.⅕H₂O

[4423] Calculated: C, 54.82; H, 4.48; Cl, 14.71; N, 8.72; S, 6.65.

[4424] Found: C, 54.77; H, 4.41; Cl, 14.71; N, 8.50; S, 6.77.

Example A-581-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[(pyridin-4-yl)acetyl]piperazineHydrochloride

[4425] In the same manner as in Example A-4, the title compound wasobtained using 4-pyridylacetic acid hydrochloride and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[4426]¹H-NMR (DMSO-d₆) δ: 2.99 (2H, br), 3.04 (2H, br), 3.57 (2H, br),3.62 (2H, br), 4.00 (2H, s), 7.71 (2H, d, J=5.9 Hz), 7.74 (1H, dd,J=8.8, 3.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.18 (1H, d, J=8.8 Hz),8.27 (1H, s), 8.29 (1H, d, J=8.8 Hz), 8.53 (1H, s), 8.72 (2H, d, J=5.9Hz).

[4427] MS (FAB) m/z: 430 [(M+H)⁺, Cl³⁵], 432 [(M+H)⁺, Cl³⁷].

[4428] Elementary analysis for C₂₁H₂₀ClN₃O₃S.HCl.0.3H₂O

[4429] Calculated: C, 53.46; H, 4.61; Cl, 15.03; N, 8.91; S, 6.80.

[4430] Found: C, 53.28; H, 4.49; Cl, 15.18; N, 8.91; S, 6.75.

Example A-591-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[4-[(3RS)-pyrrolidin-3-yl)benzoyl]piperazineHydrochloride

[4431] In the same manner as in Example A-7, the title compound wasobtained using1-[4-[(3RS)-1-tert-butoxycarbonylpyrrolidin-3-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4432]¹H-NMR (DMSO-d₆) δ: 1.85-1.95 (1H, m), 2.30-2.40 (1H, m),3.00-3.90 (13H, m), 7.72 (1H, dd, J=8.6, 2.2 Hz), 7.80 (1H, dd, J=8.8,2.0 Hz), 7.29 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz), 8.18 (1H, d,J=8.8 Hz), 8.25-8.30 (2H, m), 8.49 (1H, s).

[4433] MS (FAB) m/z: 484 [(M+H)⁺, Cl³⁵], 486 [(M+H)⁺, Cl³⁷].

[4434] Elementary analysis for C₂₅H₂₆ClN₃O₃S.HCl.{fraction (3/2)}H₂O

[4435] Calculated: C, 54.84; H, 5.52; N, 7.67; Cl, 12.95; S, 5.86.

[4436] Found: C, 55.00; H, 5.53; N, 7.48; Cl, 13.23; S, 5.97.

Example A-601-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[(1RS)-4-(pyridin-4-yl)-3-cyclohexene]carbonyl]piperazineHydrochloride

[4437] In the same manner as in Example A-4, a reaction was conductedusing (1RS)-4-(4-pyridyl)-3-cyclohexenecarboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4438]¹H-NMR (DMSO-d₆) δ: 1.50-1.60 (1H, m), 1.80-1.90 (1H, m),2.25-2.58 (5H, m), 2.80-2.90 (1H, m), 2.91-3.10 (1H, m), 3.46-3.72 (4H,m), 6.94 (1H, br s), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8,2.0 Hz), 7.96 (2H, d, J=6.8 Hz), 8.15 (1H, J=8.8 Hz), 8.24 (1H, J=2.0Hz), 8.27 (1H, J=8.8 Hz), 8.50 (1H, s), 8.76 (2H, d, J=6.8 Hz).

[4439] MS (FAB) m/z: 496 [(M+H)⁺, Cl³⁵], 498 [(M+H)⁺, Cl³⁷].

[4440] Elementary analysis for C₂₆H₂₆ClN₃O₃S.HCl.1.3H₂O

[4441] Calculated: C, 56.18; H, 5.37; Cl, 12.75; N, 7.56; S, 5.77.

[4442] Found: C, 56.03; H, 5.29; Cl, 12.67; N, 7.41; S, 5.77.

Example A-611-[(E)-4-Chlorostyrylsulfonyl]-4-[[(1RS)-4-(pyridin-4-yl)-3-cyclohexene]carbonyl]piperazineHydrochloride

[4443] In the same manner as in Example A-4, a reaction was conductedusing (1RS)-4-(4-pyridyl)-3-cyclohexenecarboxylic acid and1-[(E)-4-chlorostyrylsulfonyl)piperazine hydrochloride as startingmaterials, whereby the title compound was obtained.

[4444]¹H-NMR (DMSO-d₆) δ: 1.59-1.70 (1H, m), 1.90-1.98 (1H, m),2.31-2.56 (4H, m), 2.90-3.00 (1H, m), 3.13 (4H, br s), 3.50-3.63 (4H,m), 6.98 (1H, br s), 7.35 (1H, d, J=15.6 Hz), 7.44 (1H, d, J=15.6 Hz),7.51 (2H, d, J=8.3 Hz), 7.80 (1H, J=8.3 Hz), 7.97 (1H, J=6.8 Hz), 8.77(1H, J=6.8 Hz).

[4445] MS (FAB) m/z: 472 [(M+H)⁺, Cl³⁵], 474 [(M+H)⁺, Cl³⁷].

[4446] Calculated: C, 52.77; H, 5.81; Cl, 12.33; N, 7.69; S, 5.87.

[4447] Found: C, 52.61; H, 5.80; Cl, 12.54; N, 7.44; S, 6.05.

Example A-62 cis,trans-1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[4-(pyridin-4-yl)cyclohexane]carbonyl]piperazineHydrochloride

[4448] In the same manner as in Example A-4, a reaction was conductedusing cis, trans-4-(4-pyridyl)cyclohexanecarboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound was obtained.

[4449] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[4450] Elementary analysis for C₂₆H₂₈ClN₃O₃S.1.3HCl.2H₂O

[4451] Calculated: C, 53.71; H, 5.77; Cl, 14.02; N, 7.23; S, 5.51.

[4452] Found: C, 53.70; H, 5.70; Cl, 14.21; N, 7.13; S, 5.72.

Example A-63 cis,trans-1-[(E)-4-Chlorostyrylsulfonyl]-4-[[4-(pyridin-4-yl)cyclohexane]carbonyl]piperazineHydrochloride

[4453] In the same manner as in Example A-4, a reaction was conductedusing cis, trans-4-(4-pyridyl)cyclohexanecarboxylic acid and1-[(E)-4-chlorostyrylsulfonyl)piperazine hydrochloride as startingmaterials, whereby the title compound was obtained.

[4454] MS (FAB) m/z: 474 [(M+H)⁺, Cl³⁵], 476 [(M+H)⁺, Cl³⁷].

[4455] Elementary analysis for C₂₄H₂₈ClN₃O₃S.1.2HCl.0.8H₂O

[4456] Calculated: C, 54.17; H, 5.83; Cl, 14.66; N, 7.80; S, 6.03.

[4457] Found: C, 54.21; H, 6.20; Cl, 15.03; N, 7.51; S, 6.18.

Example A-641-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(1,2,3,6-tetrahydropyridin-4-yl)benzoyl]piperazineHydrochloride

[4458] In the same manner as in Example A-7, the title compound wasobtained using1-4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4459]¹H-NMR (DMSO-d₆) δ: 2.67 (2H, br s), 3.05 (4H, br), 3.30 (2H, brs), 3.35-3.78 (6H, m), 6.24 (1H, br s), 7.32 (2H, d, J=8.3 Hz), 7.47(2H, d, J=8.3 Hz), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, dd, J=8.8,2.0 Hz), 8.17 (1H, d, J=8.8 Hz), 8.22-8.28 (2H, m), 8.49 (1H, s), 9.25(2H, br s).

[4460] MS (FAB) m/z: 496 [(M+H)⁺, Cl³⁵], 498 [(M+H)⁺, Cl³⁷].

[4461] Elementary analysis for C₂₆H₂₆ClN₃O₃S.HCl.⅖H₂O

[4462] Calculated: C, 57.86; H, 5.19; Cl, 13.14; N, 7.79; S, 5.94.

[4463] Found: C, 57.91; H, 5.19; Cl, 12.91; N, 7.75; S, 5.78.

Example A-651-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(piperidin-4-yl)benzoyl]piperazineHydrochloride

[4464] In the same manner as in Example A-7, the title compound wasobtained using1-[4-(1-tert-butoxycarbonylpiperidin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[4465]¹H-NMR (DMSO-d₆) δ: 1.78-1.94 (4H, m), 2.80-3.21 (7H, m),3.30-3.84 (6H, m), 7.23 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.71(1H, dd, J=8.8, 2.0 Hz), 7.80 (1H, dd, J=8.8, 2.0 Hz), 8.17 (1H, d,J=8.8 Hz), 8.22-8.27 (2H, m), 8.49 (1H, s), 8.78-9.00 (2H, m).

[4466] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[4467] Elementary analysis for C₂₆H₂₈ClN₃O₃S.HCl.⅗H₂O

[4468] Calculated: C, 57.27; H, 5.58; Cl, 13.00; N, 7.71; S, 5.88.

[4469] Found: C, 57.23; H, 5.52; Cl, 12.90; N, 7.60; S, 5.83.

Example A-66(3RS)-3-[(6-Chloronaphthalen-2-yl)sulfonamido]-1-[4-(pyridin-4-yl)benzoyl]pyrrolidineHydrochloride

[4470] In saturated solution of hydrochloride in ethanol,(3RS)-1-tert-butoxycarbonyl-3-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidinewas dissolved, followed by stirring at room temperature for 8 hours. Thesolvent was then distilled off under reduced pressure. In the samemanner as in Example A-4, a reaction was conducted using the resultingresidue and 4-(4-pyridyl)benzoic acid as starting materials, whereby thetitle compound was obtained.

[4471]¹H-NMR (DMSO-d₆) δ: 1.70-2.10 (2H, m), 3.00-3.65 (4H, m),3.75-3.90 (1H, m), 7.50-8.40 (13H, m), 8.95-9.05 (2H, m).

[4472] MS (FAB) m/z: 492 [(M+H)⁺, Cl³⁵], 494 [(M+H)⁺, Cl³⁷].

[4473] Elementary analysis for C₂₆H₂₂ClN₃O₃S.HCl.1.8H₂O

[4474] Calculated: C, 55.68; H, 4.78; N, 7.49; Cl, 12.64; S, 5.72.

[4475] Found: C, 55.62; H, 4.94; N, 7.67; Cl, 12.76; S, 5.79.

Example A-67(3RS)-1-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[4-(pyridin-4-yl)benzamido]pyrrolidineHydrochloride

[4476] In saturated solution of hydrochloride in ethanol,(3RS)-1-tert-butoxycarbonyl-3-[4-(4-pyridyl)benzamido]pyrrolidine wasdissolved, followed by stirring at room temperature for 4 hours. Thesolvent was then distilled off under reduced pressure. In the samemanner as in Example A-1, a reaction was conducted using the resultingresidue and 6-chloro-2-naphthylsulfonyl chloride as starting materials,whereby the title compound was obtained as a hydrochloride.

[4477]¹H-NMR (DMSO-d₆) δ: 1.90-2.10 (2H, m), 3.00-3.60 (4H, m),4.15-4.25 (1H, m), 7.57 (1H, dd, J=8.8, 2.0 Hz), 7.73 (2H, d, J=8.8 Hz),7.85 (1H, dd, J=8.8, 2.0 Hz), 7.90 (2H, d, J=8.8 Hz), 7.95-8.05 (2H, m),8.18 (1H, d, J=8.8 Hz), 8.30-8.40 (3H, m), 8.50 (1H, s), 8.98 (2H, d,J=6.4 Hz).

[4478] MS (FAB) m/z: 492 [(M+H)⁺, Cl³⁵], 494 [(M+H)⁺, Cl³⁷].

[4479] Elementary analysis for C₂₆H₂₂ClN₃O₃S.0.8HCl.0.8H₂O

[4480] Calculated: C, 58.31; H, 4.59; N, 7.85; Cl, 11.92; S, 5.99.

[4481] Found: C, 58.27; H, 4.68; N, 7.80; Cl, 11.94; S, 6.04.

Example A-681-[[(E)-2-(6-Chloropyridin-3-yl)ethylene]sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4482] To a suspension of1-tert-butoxycarbonyl-4-[[(E)-2-(6-chloropyridin-3-yl)ethylene]sulfonyl]piperazine(390 mg) in ethanol (2 ml), saturated hydrochloric acid—ethanol (6 ml)was added, followed by stirring for 3 hours. The reaction mixture wasconcentrated and the residue was dissolved in N,N-dimethylformamide (10ml). To the resulting solution, 4-(4-pyridyl)benzoic acid hydrochloride(262 mg) and N-methylmorpholine (1.00 ml) were added. Under ice cooling,1H-benzotriazoyl-1-yloxytripyrrolidinophosphonium hexafluorophosphatewas added, followed by stirring at room temperature for 4 hours. Thereaction mixture was diluted with ethyl acetate, washed successivelywith water, a saturated aqueous solution of sodium bicarbonate andsaturated aqueous NaCl solution and then dried over anhydrous sodiumsulfate. The residue obtained by distilling off the solvent underreduced pressure was recrystallized from a mixed solvent ofdichloromethane and ethyl acetate. The resulting crystals were suspendedin ethanol. Saturated hydrochloric acid—ethanol (6 ml) was added to theresulting suspension, followed by concentration into its hydrochloride.The resulting solid was recrystallized from ethanol, whereby the titlecompound (245 mg, 47%) was obtained as a colorless solid.

[4483]¹H-NMR (DMSO-d₆) δ: 3.10-3.31 (4H, br), 3.40-3.84 (4H, br), 7.50(1H, d, J=15.9 Hz), 7.52 (1H, d, J=15.9 Hz), 7.46 (3H, d, J=8.3 Hz),8.06 (2H, d, J=8.3 Hz), 8.28-8.33 (3H, m), 8.79 (1H, d, J=2.0 Hz), 8.94(2H, d, J=6.4 Hz).

[4484] MS (FAB) m/z: 469 [(M+H)⁺, Cl³⁵], 471 [(M+H)⁺, Cl³⁷].

[4485] Elementary analysis for C₂₃H₂₁ClN₄O₃S.HCl.0.4H₂O

[4486] Calculated: C, 53.89; H, 4.48; N, 10.93; Cl, 13.83; S, 6.26.

[4487] Found: C, 53.95; H, 4.47; N, 11.02; Cl, 13.91; S, 6.39.

Example A-691-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[2-methyl-4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4488] In the same manner as in Referential Example 7, a reaction wasconducted using1-(4-bromo-2-methylbenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material, whereby the title compound was obtained.

[4489]¹H-NMR (DMSO-d₆) δ: 2.20 (3H, s), 2.80-4.00 (8H, m), 7.36 (1H, d,J=8.3 Hz), 7.73 (1H, dd, J=8.8, 2.4 Hz), 7.75-7.85 (2H, m), 7.88 (1H,s), 8.18 (1H, d, J=8.8 Hz), 8.20-8.30 (4H, m), 8.50 (1H, br s), 8.90(2H, d, J=6.8 Hz).

[4490] MS (FAB) m/z: 506 [(M+H)⁺, Cl³⁵], 508 [(M+H)⁺, Cl³⁷].

Example A-704-[4-[4[-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-3-methylphenyl]pyridineN-Oxide

[4491] In the same manner as in Example A-6, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[2-methyl-4-(pyridin-4-yl)benzoyl]piperazineas a starting material, whereby the title compound was obtained.

[4492]¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 2.80-4.20 (8H, m), 7.16 (1H, d,J=8.3 Hz), 7.38 (1H, J=8.3 Hz), 7.41 (1H, br s), 7.48 (2H, d, J=6.8 Hz),7.61 (1H, dd, J=8.8, 1.5 Hz), 7.75 (1H, d, J=8.8 Hz), 7.91-7.97 (3H, m),8.28 (2H, d, J=6.8 Hz), 8.31 (1H, br s).

[4493] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁵].

[4494] Elementary analysis for C₂₇H₂₄ClN₃O₄S.H₂O

[4495] Calculated: C, 60.05; H, 4.85; Cl, 6.56; N, 7.78; S, 5.94.

[4496] Found: C, 59.98; H, 4.89; Cl, 6.51; N, 7.48; S, 5.92.

Example A-711-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-methyl-4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4497] In the same manner as in Example A-4, a reaction was conductedusing 3-methyl-4-(4-pyridyl)benzoic acid hydrochloride as a startingmaterial, whereby the title compound was obtained.

[4498]¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 3.08 (4H, br), 3.47 (2H, br),3.72 (2H, br), 7.26-7.37 (3H, m), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.83(1H, dd, J=8.8, 2.0 Hz), 7.86 (2H, d, J=6.8 Hz), 8.18 (1H, d, J=8.8 Hz),8.25-8.29 (2H, m), 8.50 (1H, br s), 8.87 (2H, d, J=6.8 Hz)

[4499] MS (FAB) m/z: 506 [(M+H)⁺, Cl³⁵], 508 [(M+H)⁺, Cl³⁵].

[4500] Elementary analysis for C₂₇H₂₄ClN₃O₃S.0.9HCl.1.7H₂O

[4501] Calculated: C, 56.95; H, 5.01; Cl, 11.83; N, 7.38; S, 5.63.

[4502] Found: C, 57.08; H, 5.04; Cl, 11.75; N, 7.37; S, 5.49.

Example A-724-4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-piperazin-1-yl]carbonyl]-2-methylphenyl]pyridineN-Oxide

[4503] In the same manner as in Example A-6, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[3-methyl-4-(pyridin-4-yl)benzoylpiperazine as a starting material, whereby the title compound wasobtained.

[4504]¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 3.13 (4H, br), 3.63 (2H, br), 3.86(2H, br), 7.15-7.28 (5H, m), 7.60 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=8.8Hz), 7.90-7.96 (3H, m), 8.26 (2H, d, J=6.8 Hz), 8.31 (1H, s).

[4505] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁵].

[4506] Elementary analysis for C₂₇H₂₄ClN₃O₄S.H₂O

[4507] Calculated: C, 60.05; H, 4.85; Cl, 6.56; N, 7.78; S, 5.94.

[4508] Found: C, 59.71; H, 4.68; Cl, 6.87; N, 7.63; S, 5.91.

Example A-731-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazineHydrochloride

[4509] In the same manner as in Example A-4, a reaction was conductedusing 4-(2-methyl-4-pyridyl)benzoic acid hydrochloride as a startingmaterial, whereby the title compound was obtained.

[4510]¹H-NMR (DMSO-d₆) δ: 2.76 (3H, s), 3.00-3.90 (8H, m), 7.56 (2H, d,J=8.3 Hz), 7.74 (1H, dd, J=8.8, 2.4 Hz), 7.38 (1H, dd, J=8.8, 2.0 Hz),8.00 (2H, d, J=8.3 Hz), 8.14 (1H, d, J=6.4 Hz), 8.19 (1H, d, J=8.8 Hz),8.22-8.29 (3H, m), 8.51 (1H, br s), 8.80 (1H, d, J=6.4 Hz).

[4511] MS (FAB) m/z: 506 [(M+H)⁺, Cl³⁵], 508 [(M+H)⁺, Cl³⁵].

[4512] Elementary analysis for C₂₇H₂₄ClN₃O₃S.HCl.2H₂O

[4513] Calculated: C, 56.06; H, 5.05; Cl, 12.26 N. 7.26; S, 5.54.

[4514] Found: C, 55.84; H, 5.03; Cl, 12.26; N, 6.87; S, 5.54.

Example A-744-4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-Oxide

[4515] In the same manner as in Example A-6, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazineas a starting material, whereby the title compound was obtained.

[4516]¹H-NMR (CDCl₃) δ: 2.58 (3H, s), 3.13 (4H, br), 3.65 (2H, br), 3.84(2H, br), 7.34 (1H, dd, J=6.8, 2.4 Hz), 7.41 (2H, d, J=8.3 Hz), 7.45(1H, d, J=2.4 Hz), 7.56-7.62 (3H, m), 7.76 (1H, dd, J=8.8, 2.0 Hz),7.91-7.96 (3H, m), 8.28-8.32 (2H, m).

[4517] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁵].

[4518] Elementary analysis for C₂₇H₂₄ClN₃O₄S.H₂O.0.05CH₂Cl₂

[4519] Calculated: C, 59.69; H, 4.83; Cl, 7.16; N, 7.72; S, 5.89.

[4520] Found: C, 59.47; H, 4.87; Cl, 6.98; N, 7.48; S, 6.10.

Example A-754-4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[2-(morpholin-4-yl)ethylamino]carbonyl]piperazin-lyl]carbonyl]phenyl]pyridineN-Oxide

[4521] In the same manner as in Example A-4, a reaction was conductedusing4-[4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenylpyridineN-Oxide and 4-(2-aminoethyl)morpholine as starting materials, wherebythe title compound was obtained.

[4522]¹H-NMR (CDCl₃) δ: 2.22 (4H, s), 2.35-2.80 (6H, br), 3.20-3.90 (3H,br), 3.74 (4H, s), 4.20-4.60 (1H, br), 5.25-5.50 (1H, br), 6.80-7.20(1H, br), 7.45-7.70 (7H, m), 7.76 (1H, d, J=8.8 Hz), 7.85-7.95 (3H, m),8.26 (2H, d, J=6.9 Hz), 8.32 (1H, s).

[4523] MS (FAB) m/z: 664 [(M+H)⁺, Cl³⁵], 666 [(M+H)⁺, Cl³⁷].

Example A-764-4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[2-(dimethylamino)ethylamino]carbonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4524] In the same manner as in Example A-4, a reaction-was conductedusing4-[4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide and 2-(dimethylamino)ethylamine as starting materials, wherebythe title compound was obtained.

[4525]¹H-NMR (CDCl₃) δ: 2.29 (6H, s), 2.35-2.75 (6H, br), 3.35-3.90 (3H,br), 4.40-4.60 (1H, br), 5.25-5.50 (1H, br), 7.00-7.20 (1H, br),7.45-7.65 (7H, m), 7.77 (1H, dd, J=8.8, 1.4 Hz), 7.85-7.95 (3H, m), 8.26(2H, d, J=7.3 Hz), 8.34 (1H, s).

[4526] MS (FAB) m/z: 622 [(M+H)⁺, Cl³⁵], 624 [(M+H)⁺, Cl³⁵].

[4527] Elementary analysis for C₃₁H₃₂N₅O₅S.0.05CH₂Cl₂.2H₂O

[4528] Calculated: C, 56.30; H, 5.49; N, 10.57; Cl, 5.89; S, 4.84.

[4529] Found: C, 56.27; H, 5.37; N, 10.39; Cl, 6.01; S, 4.91.

Example A-774-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-methoxycarbonylmethyl-1-[4-(pyridin-2-yl)benzoyl]piperazine

[4530] In the same manner as in Example A-68, a reaction was conductedusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-methoxycarbonylmethylpiperazine(723 mg) and 4-(2-pyridyl)benzoic acid hydrochloride as startingmaterials, whereby the title compound was obtained.

[4531]¹H-NMR (DMSO-d₆) δ: 2.30-4.50 (11H, m), 5.06 (1H, br s), 7.30-7.50(3H, m), 7.72 (1H, dd, J=8.8, 2.0 Hz), 7.80-7.85 (1H, m), 7.85-7.95 (1H,m), 7.98 (1H, d, J=7.8 Hz), 8.10 (2H, d, J=8.3 Hz), 8.18 (1H, d, J=8.8Hz), 8.25-8.30 (2H, m), 8.51 (1H, s), 8.65-8.70 (1H, m).

[4532] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁵].

[4533] Elementary analysis for C₂₉H₂₆ClN₃O₅S.1.1H₂O

[4534] Calculated: C, 59.66; H, 4.87; N, 7.20; Cl, 6.07; S, 5.49.

[4535] Found: C, 59.53; H, 4.61; N, 7.05; Cl, 6.33; S, 5.70.

Example A-784-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-carboxymethyl-1-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4536] In the same manner as in Example A-3, a reaction was conductedusing4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-methoxycarbonylmethyl-1-[4-(pyridin-2-yl)benzoyl]piperazineas a starting material, whereby the title compound was obtained.

[4537]¹H-NMR (DMSO-d₆) δ: 2.30-4.50 (8H, m), 5.05 (1H, br s), 7.35-7.40(1H, m), 7.43 (2H, d, J=8.8 Hz), 7.72 (1H, d, J=8.3 Hz), 7.81 (1H, d,J=8.8 Hz), 7.85-7.90 (1H, m), 7.97 (1H, d, J=7.8 Hz), 8.08 (2H, d, J=8.8Hz), 8.17 (1H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.49 (1H, s), 8.65-8.70(1H, m).

[4538] MS (FAB) m/z: 550 [(M+H)⁺, Cl³⁵], 552 [(M+H)⁺, Cl³⁵].

[4539] Elementary analysis for C₂₈H₂₄ClN₃O₅S.0.4HCl.0.9H₂O

[4540] Calculated: C, 57.90; H, 4.55; N, 7.23; Cl, 8.55; S, 5.52.

[4541] Found: C, 57.76; H, 4.26; N, 7.02; Cl, 8.44; S, 5.27.

Example A-792-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4542] In the same manner as in Example A-35, a reaction was conductedusing4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-carboxymethyl-1-[4-(pyridin-2-yl)benzoyl]piperazineas a starting material, whereby the title compound was obtained.

[4543]¹H-NMR (DMSO-d₆) δ: 2.20-4.50 (8H, m), 5.10 (1H, br s), 6.96 (2H,br s), 7.45-7.55 (3H, m), 7.70-7.85 (3H, m), 8.05-8.35 (6H, m), 8.50(1H, s), 8.81 (1H, d, J=4.9 Hz).

[4544] MS (FAB) m/z: 549 [(M+H)⁺, Cl³⁵], 551 [(M+H)⁺, Cl³⁵].

[4545] Elementary analysis for C₂₈H₂₅ClN₄O₄S.1.3HCl.1.5H₂O

[4546] Calculated: C, 53.94; H, 4.74; N, 8.99; Cl, 13.08; S, 5.14.

[4547] Found: C, 53.85; H, 4.87; N, 8.80; Cl, 13.19; S, 5.27.

Example A-801-[(Z)-4-Chloro-β-(2-hydroxyethan-1-yl)-β-styrylsulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4548] Under ice cooling,4-tert-butoxycarbonyl-1-[(Z)-4-chloro-β-[2-(methoxymethyloxy)ethyl]-β-styrylsulfonyl]piperazine(355 mg) was dissolved in ethanol (3 ml), followed by the addition ofsaturated solution of hydrochloride (6 ml) in ethanol. The resultingmixture was stirred at room temperature for 1 hour. After the reactionmixture was concentrated under reduced pressure, a reaction was effectedin the same manner as in Example A-4 by using the resulting residue,whereby the title compound (285 mg, 65%) was obtained.

[4549]¹H-NMR (DMSO-d₆) δ: 2.58 (2H, t, J=6.6 Hz), 3.06 (4H, br s),3.15-3.60 (4H, br), 3.68 (2H, t, J=6.6 Hz), 7.24 (1H, s), 7.38 (2H, d,J=8.6 Hz), 7.40 (2H, d, J=8.6 Hz), 7.47-7.57 (3H, m), 8.02-8.10 (2H, m),8.14 (2H, d, J=8.3 Hz), 8.74 (1H, d, J=4.4 Hz).

[4550] MS (FAB) m/z: 512 (M+H)⁺.

Example A-811-[(E)-4-Chloro-β-(2-hydroxyethan-1-yl)-β-styrylsulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4551] In the same manner as in Example A-80, the title compound (240mg, 74%) was obtained using4-tert-butoxycarbonyl-1-[(E)-4-chloro-β-[2-(methoxymethyloxy)ethyl]-β-styrylsulfonyl]piperazine(355 mg) as a starting material.

[4552]¹H-NMR (DMSO-d₆) δ: 2.74 (2H, t, J=7.3 Hz), 3.27 (4H, br s),3.37-3.85 (6H, m), 7.45 (1H, s), 7.50-7.60 (5H, m), 7.68 (2H, d, J=8.3Hz), 8.06-8.17 (4H, m), 8.75 (1H, d, J=4.9 Hz).

[4553] MS (FAB) m/z: 512 (M+H)⁺.

[4554] Elementary analysis for C₂₆H₂₆ClN₃O₄S.1.1HCl.0.8H₂O

[4555] Calculated: C, 55.12; H, 5.11; N, 7.42; Cl, 13.14; S, 5.66.

[4556] Found: C, 55.22; H, 5.21; N, 7.20; Cl, 12.97; S, 5.66.

[4557] In the same manner as in Example A-7 or Example A-1, thecompounds shown in Examples A-82 to A-86 were synthesized.

Example A-821-[(6-Chloro-1-phenylsulfonylindol-2-y)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4558]¹H-NMR (CDCl₃) δ: 2.80-4.30 (8H, br), 7.34 (1H, d, J=8.5, 1.7 Hz),7.43-7.62 (9H, m), 7.69 (2H, d, J=7.8 Hz), 8.04 (2H, d, J=7.8 Hz), 8.33(1H, s), 8.70 (2H, br s).

[4559] Elementary analysis for C₃₀H₂₅ClN₄O₅S₂

[4560] Calculated: C, 58.01; H, 4.06; Cl, 5.71; N, 9.02; S, 10.32.

[4561] Found: C, 58.34; H, 4.23; Cl, 5.78; N, 8.85; S, 9.96.

Example A-831-[(5-Chloro-3-methylbenzo[b]thien-2-yl)sulfonyl]-4-[4-(piridin-4-yl)benzoyl]piperazine

[4562]¹H-NMR (DMSO-d₆) δ: 2.67 (3H, s), 3.15-3.31 (4H, br), 3.37-3.84(4H, br), 7.58 (1H, m), 7.65 (1H, dd, J=8.8, 2.0 Hz), 7.92-8.03 (2H,br), 8.13 (1H, d, J=2.0 Hz), 8.15-8.24 (4H, m), 8.79-8.92 (2H, br).

[4563] MS (FAB) m/z: 512 [(M+H)⁺, Cl³⁵], 514 [(M+H)⁺, Cl³⁷].

[4564] Elementary analysis for C₂₅H₂₂ClN₃O₃S₂.HCl.0.3H₂O

[4565] Calculated: C, 54.21; H, 4.29; Cl, 12.80; N, 7.59; S, 11.58.

[4566] Found: C, 54.25; H, 4.25; Cl, 12.98; N, 7.52; S, 11.52.

Example A-841-[(1-Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4567]¹H-NMR (CDCl₃) δ: 0.25 (9H, s), 3.35-4.00 (8H, m), 7.43 (2H, t,J=8.1 Hz), 7.47-7.64 (7H, m), 7.64-7.74 (3H, m), 8.00 (2H, d, J=8.1 Hz),8.23 (1H, d, J=8.8 Hz), 8.71 (2H, br s).

Example A-851-[(5-Chlorobenzo[b]furan-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4568]¹H-NMR (DMSO-d₆) δ: 3.20-3.55 (6H, br), 3.60-3.90 (2H, br), 7.61(1H, dd, J=8.8, 2.0 Hz), 7.61 (2H, d, J=8.8 Hz), 7.68 (1H, s), 7.84 (1H,d, J=8.8 Hz), 7.94 (1H, d, J=2.0 Hz), 8.05 (2H, d, J=8.8 Hz), 8.34 (2H,d, J=5.9 Hz), 8.95 (2H, d, J=5.9 Hz).

[4569] MS (FAB) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

[4570] Elementary analysis for C₂₄H₂₀ClN₃O₄S.HCl.0.6H₂O

[4571] Calculated: C, 54.47; H, 4.23; Cl, 13.40; N, 7.94; S, 6.06.

[4572] Found: C, 54.48; H, 4.14; Cl, 13.41; N, 7.83; S, 6.17.

Example A-861-[(6-Chlorobenzo[b]furan-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4573]¹H-NMR (DMSO-d₆) δ: 3.20-3.45 (4H, br), 3.35-3.55 (2H, br),3.65-3.85 (2H, br), 7.48 (1H, d, J=8.8 Hz), 7.59 (2H, d, J=7.8 Hz), 7.73(1H, s), 7.80-8.10 (1H, m), 7.86 (1H, d, J=8.8 Hz), 7.98 (1H, s), 8.04(2H, d, J=7.8 Hz), 8.20-8.32 (½H, m), 8.60-9.49 (1H, br), 8.90-8.93 (½H,m).

[4574] MS (FAB) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

[4575] Elementary analysis for C₂₄H₂₀ClN₃O₄S.HCl.0.3H₂O

[4576] Calculated: C, 55.03; H, 4.16; Cl, 13.54; N, 8.02; S, 6.12.

[4577] Found: C, 55.06; H, 4.12; Cl, 13.62; N, 7.89; S, 6.11.

[4578] In the same manner as in Example A-7 or Example A-4, thecompounds shown in Examples A-87 to A-93 were synthesized.

Example A-871-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4579]¹H-NMR (CDCl₃) δ: 3.45-3.53 (4H, br), 3.53-3.98 (4H, br),7.40-7.50 (4H, m), 7.52-7.60 (6H, m), 7.70 (2H, d, J=8.3 Hz), 8.01 (2H,d, J=8.3 Hz), 8.24 (1H, d, J=9.3 Hz), 8.73 (2H, br).

[4580] MS (FAB) m/z: 621 [(M+H)⁺, Cl³⁵], 623 [(M+H)⁺, Cl³⁷].

[4581] Elementary analysis for C₃₀H₂₅ClN₄O₅S₂.0.1CH₂Cl₂

[4582] Calculated: C, 57.42; H, 4.03; Cl, 6.76; N, 8.90; S, 10.19.

[4583] Found: C, 57.10; H, 4.35; Cl, 6.58; N, 8.80; S, 10.04.

Example A-881-[(1-Phenylsulfonyl-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4584]¹H-NMR (CDCl₃) δ: 3.43-3.53 (4H, br), 3.53-3.94 (4H, br), 7.43(1H, t, J=7.6 Hz), 7.40-7.46 (2H, m), 7.48-7.65 (10H, m), 7.69 (2H, d,J=8.3 Hz), 8.04 (3H, m), 8.30 (1H, d, J=8.3 Hz), 8.69 (2H, m).

[4585] MS (FAB) m/z: 587 (M+H)⁺

[4586] Elementary analysis for C₃₀H₂₆N₄O₅S₂.0.5H₂O

[4587] Calculated: C, 60.49; H, 4.57; N, 9.41; S, 10.77.

[4588] Found: C, 60.32; H, 4.73; N, 9.41; S, 10.43.

Example A-891-[(1-Phenylsulfonyl-5-chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]homopiperazine

[4589]¹H-NMR (CDCl₃) δ: 1.85-1.92 (1H, m), 2.13-2.20 (1H, m), 3.47-3.76(1H, m), 3.54-3.73 (5H, m), 3.87-3.98 (2H, m), 7.38-7.60 (11H, m), 7.69(2H, d, J=6.8 Hz), 8.02-8.08 (2H, m), 8.18-8.23 (1H, m), 8.69 (2H, d,J=5.9 Hz).

[4590] MS (FAB) m/z: 635 [(M+H)⁺, Cl³⁵], 637 [(M+H)⁺, Cl³⁷].

Example A-901-[(5-Chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4591]¹H-NMR (DMSO-d₆) δ: 2.92-3.26 (4H, br), 3.35-3.78 (4H, br), 7.03(1H, d, J=2.0 Hz), 7.34 (1H, dd, J=8.8, 2.4 Hz), 7.47-7.56 (4H, m), 7.80(1H, d, J=2.0 Hz), 8.02-8.16 (4H, m), 8.73 (1H, d, J=4.9 Hz), 12.40-(1H,s).

[4592] MS (FAB) m/z: 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

[4593] Elementary analysis for C₂₄H₂₁ClN₄O₃S.0.9HCl.1.6H₂O

[4594] Calculated: C, 53.13; H, 4.66; Cl, 12.41; N, 10.33; S, 5.91.

[4595] Found: C, 53.29; H, 4.89; Cl, 12.40; N, 10.15; S, 5.92.

Example A-911-[(5-Chloro-1-methylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4596]¹H-NMR (CDCl₃) δ: 3.09-3.45 (4H, br), 3.49-4.03 (4H, br), 3.70(3H, s), 7.08 (1H, m), 7.33 (1H, d, J=8.8 Hz), 7.37 (2H, d, J=7.8 Hz),7.44-7.53 (3H, m), 7.64-7.69 (3H, m), 8.69 (2H, br).

[4597] MS (FAB) m/z: 495 [(M+H)⁺, Cl³⁵], 497 [(M+H)⁺, Cl³⁷].

[4598] Elementary analysis for C₂₅H₂₃ClN₄O₃S.0.1HCl.0.2H₂O

[4599] Calculated: C, 56.12; H, 4.60; Cl, 13.25; N, 10.47; S, 5.99.

[4600] Found: C, 56.13; H, 4.54; Cl, 13.25; N, 10.40; S, 5.99.

Example A-921-[(5-Chloro-1-ethylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4601]¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.8 Hz), 3.15-3.37 (4H, br),3.38-3.57 (2H, br), 3.65-3.87 (2H, br), 4.47 (2H, q, J=6.8 Hz), 7.17(1H, s), 7.41 (1H, dd, J=8.8, 2.0 Hz), 7.63 (2H, d, J=8.3 Hz), 7.73 (1H,d, J=8.8 Hz), 7.81 (1H, d, J=2.0 Hz), 8.05 (2H, d, J=8.3 Hz), 8.31 (2H,d, J=6.4 Hz), 8.94 (2H, d, J=6.4 Hz).

[4602] MS (FAB) m/z: 509 [(M+H)⁺, Cl³⁵], 511 [(M+H)⁺, Cl³⁷].

[4603] Elementary analysis for C₂₆H₂₅ClN₄O₃S.1.1HCl.1.2H₂O

[4604] Calculated: C, 54.71; H, 5.03; Cl, 13.04; N, 9.82; S, 5.62.

[4605] Found: C, 54.51; H, 5.11; Cl, 13.06; N, 9.68; S, 5.71.

Example A-931-[(5-Chloro-1-ethoxycarbonylmethylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4606]¹H-NMR (DMSO-d₆) δ: 1.19 (3H, t, J=6.8 Hz), 3.00-3.29 (4H, br),3.30-3.85 (4H, br), 4.14 (2H, q, J=6.8 Hz), 5.30 (2H, s), 7.17-7.27 (1H,m), 7.42 (1H, d, J=8.8 Hz), 7.59 (2H, d, J=7.8 Hz), 7.73 (1H, d, J=8.8Hz), 7.84 (1H, s), 8.01 (2H, d, J=7.8 Hz), 8.21 (2H, d, J=6.3 Hz), 8.88(2H, d, J=6.3 Hz).

[4607] MS (FAB) m/z: 567 [(M+H)⁺, Cl³⁵], 569 [(M+H)⁺, Cl³⁷].

[4608] Elementary analysis for C₂₈H₂₇ClN₄O₅S.0.9HCl.0.5H₂O

[4609] Calculated C, 55.23; H, 4.78; Cl, 11.06; N, 9.20; S, 5.27.

[4610] Found: C, 54.91; H, 5.06; Cl, 10.78; N, 9.22; S, 5.45.

[4611] In the same manner as in Example A-4, the compounds shown inExamples A-94 to A-98 were synthesized.

Example A-941-[(5-Chlorobenzothiazol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4612]¹H-NMR (DMSO-d₆) δ: 3.28-3.90 (8H, m), 7.61 (2H, d, J=8.3 Hz),7.77 (1H, dd, J=8.8, 2.0 Hz), 8.04 (2H, d, J=8.8 Hz), 8.28 (2H, d, J=6.4Hz), 8.38 (1H, d, J=8.8 Hz), 8.43 (1H, d, J=2.0 Hz), 8.93 (2H, d, J=6.4Hz)

[4613] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

[4614] Elementary analysis for C₂₃H₁₉ClN₄O₃S₂.HCl.0.6H₂O

[4615] Calculated: C, 50.57; H, 3.91; Cl, 12.98; N, 10.26; S, 11.74.

[4616] Found: C, 50.72; H, 3.90; Cl, 13.22; N, 9.99; S, 11.35.

Example A-951-[(6-Chlorobenzothiazol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4617]¹H-NMR (DMSO-d₆) δ: 3.28-3.90 (8H, m), 7.55 (2H, d, J=8.3 Hz),7.77 (1H, dd, J=8.8, 2.0 Hz), 7.85-7.93 (4H, m), 8.29 (1H, d, J=8.8 Hz),8.50 (1H, d, J=2.0 Hz), 8.73 (2H, d, J=6.4 Hz).

[4618] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

[4619] Elementary analysis for C₂₃H₁₉ClN₄O₃S₂.0.25HCl.0.5H₂O

[4620] Calculated: C, 53.42; H, 3.95; Cl, 8.57; N, 10.83; S, 12.40.

[4621] Found: C, 53.22; H, 3.91; Cl, 8.41; N, 10.70; S, 12.59.

Example A-961-[(5-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4622]¹H-NMR (DMSO-d₆) δ: 3.02-4.00 (8H, m), 7.51 (2H, d, J=8.8 Hz),7.62 (1H, dd, J=8.8, 2.0 Hz), 7.71 (2H, d, J=5.4 Hz), 7.82 (2H, d, J=8.8Hz), 8.04 (1H, s), 8.17 (1H, d, J=2.0 Hz), 8.19 (1H, d, J=8.8 Hz), 8.65(2H, d, J=5.4 Hz).

[4623] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

[4624] Elementary analysis for C₂₄H₂₀ClN₃O₃S₂.HCl

[4625] Calculated: C, 53.93; H, 3.96; Cl, 13.27; N, 7.86; S, 12.00.

[4626] Found: C, 53.79; H, 4.07; Cl, 13.37; N, 7.70; S, 12.07.

Example A-971-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[4627]¹H-NMR (DMSO-d₆) δ: 3.03-3.88 (8H, m), 7.56-7.61 (3H, m), 8.02(2H, d, J=8.8 Hz), 8.09 (2H, d, J=8.8 Hz), 8.29 (2H, d, J=6.3 Hz), 8.34(1H, d, J=2.0 Hz), 8.94 (2H, d, J=6.3 Hz).

[4628] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[4629] Elementary analysis for C₂₄H₂₀ClN₃O₃S₂.HCl.H₂O

[4630] Calculated: C, 52.17; H, 4.20; Cl, 12.83; N, 7.61; S, 11.61.

[4631] Found: C, 52.18; H, 4.14; Cl, 12.84; N, 7.56; S, 11.70.

Example A-981-[(6-Chlrobenzo[b]thien-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazineHydrochloride

[4632]¹H-NMR (DMSO-d₆) δ: 3.02-3.90 (8H, m), 7.55 (2H, d, J=8.3 Hz),7.58 (1H, dd, J=8.3, 1.5 Hz), 7.62 (1H, t, J=6.3 Hz), 8.07-8.20 (6H, m),8.33 (1H, d, J=1.5 Hz), 8.77 (1H, d, J=5.4 Hz).

[4633] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[4634] Elementary analysis for C₂₄H₂₀ClN₃O₃S₂.HCl.0.8H₂O

[4635] Calculated: C, 52.52; H, 4.15; Cl, 12.92; N, 7.66; S, 11.68.

[4636] Found: C, 52.69; H, 4.18; Cl, 12.63; N, 7.46; S, 11.68.

Example A-991-[(6-Chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4637] In tetrahydrofuran (4.0 ml),1-[(1-phenylsulfonyl-6-chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine(380 mg) was dissolved, followed by the addition of methanol (4.0 ml)and potassium hydroxide (34.3 mg) at room temperature. The resultingmixture was stirred for 2 hours. To the reaction mixture, a saturatedaqueous solution (30 ml) of ammonium chloride was added to make itweakly acidic. Then, a saturated aqueous solution (40 ml) of sodiumbicarbonate was added to make the resulting mixture to weakly alkaline.The resulting mixture was added with dichloromethane (30 ml). Theorganic layer thus separated was extracted further with dichloromethane.The organic layers were combined, dried over anhydrous sodium sulfateand distilled under reduced pressure. The residue thus obtained waspurified by preparative thin-layer chromatography on a silica gel(dichloromethane:acetone:methanol=20:2:1), followed by recrystallizationfrom a mixed solvent of hexane and dichloromethane, whereby the titlecompound (157 mg, 53%) was obtained as a white solid.

[4638]¹H-NMR (CDCl₃) δ: 2.70-4.20 (8H, br), 7.02 (1H, br s), 7.23 (1H,dd, J=8.3, 1.8 Hz), 7.42-7.50 (5H, m), 7.62-7.68 (3H, m), 8.69 (2H, d,J=5.9 Hz), 8.78 (1H, br s).

[4639] In the same manner as in Example A-99, the compounds shown inExamples A-100 to A-103 were synthesized.

Example A-1001-[(Indol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4640]¹H-NMR (DMSO-d₆) δ: 3.00-3.20 (4H, br), 3.42-3.84 (4H, br), 7.05(1H, s), 7.16 (1H, t, J=7.3 Hz), 7.33 (1H, m), 7.50 (3H, m), 7.72 (2H,d, J=6.3 Hz), 7.82 (2H, d, J=7.8 Hz), 7.65 (2H, d, J=4.9 Hz), 12.20 (1H,s).

[4641] MS (FAB) m/z: 447 (M+H)⁺

[4642] Elementary analysis for C₂₄H₂₂N₄O₃S.0.2H₂O

[4643] Calculated: C, 64.04; H, 5.02; N, 12.45; S, 7.12.

[4644] Found: C, 64.23; H, 5.30; N, 12.06; S, 7.07.

Example A-1011-[(5-Chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4645]¹H-NMR (DMSO-d₆) δ: 2.94-3.25 (4H, br), 3.30-3.41 (4H, br), 7.03(1H, s), 7.33 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=8.8 Hz), 7.59 (2H, d,J=7.3 Hz), 7.80 (1H, s), 8.03 (2H, d, J=7.3 Hz), 8.33 (2H, d, J=5.9 Hz),8.95 (2H, d, J=5.9 Hz), 12.5 (1H, s).

[4646] MS (FAB) m/z: 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

[4647] Elementary analysis for C₂₄H₂₁ClN₄O₃S.HCl.1.5H₂O

[4648] Calculated: C, 52.95; H, 4.63; Cl, 13.02; N, 10.29; S, 5.89.

[4649] Found: C, 53.34; H, 4.74; Cl, 12.87; N, 9.92; S, 5.77.

Example A-1021-[(5-Chloroindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]homopiperazine

[4650]¹H-NMR (DMSO-d₆) δ: 1.75-1.85 (1H, br), 2.02-2.13 (1H, br),3.50-3.73 (6H, m), 3.92-3.96 (1H, br), 7.00 (1H, m), 7.28-7.35 (1H, m),7.43-7.52 (2H, m), 7.58 (1H, d, J=7.8 Hz), 7.74-7.78 (1H, m), 7.93-8.07(2H, m), 8.14-8.36 (2H, m), 8.83-8.95 (2H, m), 12.43 (1H, m).

[4651] MS (FAB) m/z: 495 [(M+H)⁺, Cl³⁵], 497 [(M+H)⁺, Cl³⁷].

[4652] Elementary analysis for C₂₅H₂₃ClN₄O₃S.1.05HCl.0.85H₂O

[4653] Calculated: C, 54.73; H, 4.73; Cl, 13.25; N, 10.21; S, 5.85.

[4654] Found: C, 55.04; H, 5.03; Cl, 13.23; N, 9.89; S, 5.61.

Example A-1031-[(5-Ethynylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4655]¹H-NMR (CDCl₃) δ: 2.85-3.40 (4H, br), 3.06 (1H, s), 3.40-4.10 (4H,br), 7.01 (1H, br s), 7.39 (1H, d, J=8.8 Hz), 7.45 (2H, d, J=8.3 Hz),7.45-7.50 (3H, m), 7.64 (2H, d, J=8.3 Hz), 7.89 (1H, br s), 8.70 (2H, d,J=6.8 Hz), 9.55 (1H, br s).

[4656] MS (FAB) m/z: 471 (M+H)⁺

Example A-104cis-4-[(5-Chloroindol-2-yl)sulfonyl]-2,6-dimethyl-1-[4-(pyridin-4-yl)benzoyl]piperazine

[4657] In tetrahydrofuran (50 ml),cis-1-(4-Bromobenzoyl)-4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(4-bromobenzoyl)-2,6-dimethylpiperazine(800 mg), diethyl 4-pyridylbolan (255 mg), tetrabutylammonium bromide(275 mg) and tetrakis(triphenylphosphine) palladium (0) (175 mg) weredissolved, followed by the addition of potassium hydroxide (289 mg) andwater (0.745 ml). The resulting mixture was heated under reflux for 3hours. The reaction mixture was concentrated under reduced pressure.Ethyl acetate and water were added to the residue to separate theorganic layer. The organic layer thus obtained was washed with saturatedaqueous NaCl solution, dried over anhydrous sodium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (2%methanol—dichloromethane), followed by crystallization from ethanol,whereby the title compound (580 mg, 53%) was obtained as colorlessamorphous.

[4658]¹H-NMR (DMSO-d₆) δ: 1.33 (6H, br), 2.60-2.70 (2H, m), 3.40-3.60(2H, m), 3.70-4.10 (1H, br), 4.40-4.90 (1H, br), 7.02 (1H, s), 7.30-7.35(1H, m), 7.45-7.55 (3H, m), 7.72 (2H, d, J=5.4 Hz), 7.75-7.85 (3H, m),8.65 (2H, d, J=5.4 Hz), 12.43 (1H, s).

[4659] Elementary analysis for C₂₆H₂₅ClN₄O₃S.0.3H₂O

[4660] Calculated: C, 60.70; H, 5.02; Cl, 6.89; N, 10.89; S, 6.23.

[4661] Found: C, 61.03; H, 5.06; Cl, 7.09; N, 10.51; S, 6.09.

Example A-1051-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[4662] In a mixed solvent of dimethoxyethane (10 ml) and methanol (10ml),1-[(5-bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(485 mg) and 4-pyridylboric acid (197 mg) were suspended at roomtemperature, followed by the successive addition oftetrakis(triphenylphosphine) palladium (0) (116 mg) and cesium fluoride(1.00 g). The resulting mixture was heated under reflux for 1 week.After the reaction mixture was cooled to room temperature, it wasconcentrated under reduced pressure. Dichloromethane and water wereadded to the concentrate to separate the organic layer. The organiclayer thus obtained was dried over anhydrous sodium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (2%methanol—dichloromethane). The pale yellow crystals precipitated inethanol were collected by filtration and dissolved in dichloromethane.To the resulting solution, 1N aqueous hydrochloride in ethanol was addedand the resulting mixture was distilled under reduced pressure to removethe solvent. The yellow crystals precipitated in ethyl acetate werecollected by filtration and dried, whereby the title compound (40%) wasobtained.

[4663]¹H-NMR (DMSO-d₆) δ: 2.96 (2H, br s), 3.16 (2H, br s), 3.38 (2H, brs), 3.81 (2H, br s), 7.05 (1H, d, J=2.0 Hz), 7.35 (1H, dd, J=8.8, 2.0Hz), 7.51 (1H, d, J=8.8 Hz), 7.81 (1H, d, J=2.0 Hz), 8.13 (2H, d, J=5.9Hz), 8.87 (2H, d, J=5.9 Hz), 9.37 (2H, s), 12.48 (1H, s).

[4664] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

[4665] Elementary analysis for C₂₂H₁₉ClN₆O₃S.0.9HCl.1.4H₂O

[4666] Calculated: C, 48.84; H, 4.23; Cl, 12.45; N, 15.53; S, 5.93.

[4667] Found: C, 49.11; H, 4.27; Cl, 12.26; N, 15.34; S, 5.91.

[4668] In the same manner as in Example A-6, the compounds shown inExamples A-106 to A-120 were synthesized.

Example A-1064-[4-[[4-[(6-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4669]¹H-NMR (CDCl₃) δ: 2.90-4.10 (8H, br), 7.02 (1H, d, J=1.0 Hz), 7.22(1H, dd, J=8.8, 1.7 Hz), 7.46 (2H, d, J=8.3 Hz), 7.47 (1H, s), 7.50 (2H,d, J=7.3 Hz), 7.60 (2H, d, J=8.3 Hz), 8.63 (1H, d, J=8.8 Hz), 8.29 (2H,d, J=7.3 Hz), 9.32 (1H, br s).

[4670] Elementary analysis for C₂₄H₂₁ClN₄O₄S.1.7H₂O

[4671] Calculated: C, 54.64; H, 4.66; Cl, 6.72; N, 10.62; S, 6.08.

[4672] Found: C, 54.63; H, 4.65; Cl, 6.91; N, 10.42; S, 6.07.

Example A-1074-[4-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide

[4673]¹H-NMR (DMSO-d₆) δ: 3.00-3.20 (4H, br), 3.34-3.58 (2H, br),3.60-3.84 (2H, br), 7.03 (1H, s), 7.34 (1H, d, J=8.8 Hz), 7.47 (2H, d,J=7.3 Hz), 7.51 (1H, d, J=8.8 Hz), 7.79 (2H, d, J=5.9 Hz), 7.80 (1H, s),7.81 (2H, d, J=7.3 Hz), 8.28 (2H, d, J=5.9 Hz), 12.43 (1H, br).

[4674] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

[4675] Elementary analysis for C₂₄H₂₁ClN₄O₄S.0.2H₂O

[4676] Calculated: C, 57.59; H, 4.31; Cl, 7.08; N, 11.19; S, 6.41.

[4677] Found: C, 57.60; H, 4.38; Cl, 7.26; N, 11.09; S, 6.16.

Example A-1084-[4-[[4-[(5-Chloro-1-methylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4678]¹H-NMR (CDCl₃) δ: 3.06-3.45 (4H, br), 3.48-4.06 (4H, br), 4.00(3H, s), 7.07 (1H, m), 7.33 (1H, d, J=8.8 Hz), 7.35 (2H, dd, J=8.8, 1.8Hz), 7.45-7.57 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.66 (1H, d, J=2.0 Hz),8.27 (2H, d, J=6.8 Hz).

[4679] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

[4680] Elementary analysis for C₂₅H₂₃ClN₄O₄S.0.9H₂O.0.05CH₂Cl₂

[4681] Calculated: C, 56.61; H, 4.72; Cl, 7.34; N, 10.54; S, 6.03.

[4682] Found: C, 56.51; H, 4.71; Cl, 7.51; N, 10.37; S, 6.29.

Example A-1092-[4-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4683]¹H-NMR (DMSO-d₆) δ: 3.04-3.18 (4H, br), 3.37-3.83 (4H, br), 7.03(1H, s), 7.33 (1H, d, J=8.8 Hz), 7.38-7.44 (2H, m), 7.45 (2H, d, J=7.3Hz), 7.50 (1H, d, J=8.8 Hz), 7.61-7.67 (1H, m), 7.80 (1H, s), 7.85 (2H,d, J=7.3 Hz), 8.33 (1H, m), 12.40 (1H, br).

[4684] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

[4685] Elementary analysis for C₂₄H₂₁ClN₄O₄S.0.2H₂O

[4686] Calculated: C, 57.59; H, 4.31; Cl, 7.08; N, 11.19; S, 6.41.

[4687] Found: C, 57.72; H, 4.58; Cl, 7.13; N, 10.86; S, 6.29.

Example A-1104-[4-[[4-[(5-Chloro-1-ethylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4688]¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.8 Hz), 3.18-3.38 (4H, br),3.40-3.61 (2H, br), 3.62-3.84 (2H, br), 4.46 (2H, q, J=6.8 Hz), 7.16(1H, s), 7.41 (1H, dd, J=8.8, 2.0 Hz), 7.52 (2H, d, J=7.3 Hz), 7.72 (1H,d, J=8.8 Hz), 7.78-7.88 (5H, m), 8.28 (2H, d, J=7.3 Hz).

[4689] MS (FAB) m/z: 525 [(M+H)⁺, Cl³⁵], 527 [(M+H)⁺, Cl³⁷].

[4690] Elementary analysis for C₂₆H₂₅ClN₄O₄S.0.4H₂O

[4691] Calculated: C, 58.67; H, 4.89; Cl, 6.66; N, 10.53; S, 6.02.

[4692] Found: C, 58.73; H, 4.91; Cl, 6.88; N, 10.26; S, 5.96.

Example A-1114-[4-[[4-[(5-Chloro-3-methylbenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4693]¹H-NMR (DMSO-d₆) δ: 2.67 (3H, s), 3.12-3.29 (4H, br), 3.37-3.86(4H, br), 7.48 (2H, d, J=8.3 Hz), 7.65 (1H, dd, J=8.8, 2.0 Hz), 7.80(2H, d, J=7.3 Hz), 7.81 (2H, d, J=8.3 Hz), 8.12 (1H, d, J=2.0 Hz), 8.15(1H, d, J=8.8 Hz), 8.27 (2H, d, J=7.3 Hz).

[4694] MS (FAB) m/z: 528 [(M+H)⁺, Cl³⁵], 530 [(M+H)⁺, Cl³⁷].

[4695] Elementary analysis for C₂₅H₂₂ClN₃O₄S₂.0.7H₂O

[4696] Calculated: C, 55.54; H, 4.36; Cl, 6.56; N, 7.77; S, 11.86.

[4697] Found: C, 55.73; H, 4.40; Cl, 6.67; N, 7.52; S, 11.72.

Example A-1124-[4-[[cis-4-[(5-Chloroindol-2-yl)sulfonyl]-2,6-dimethylpiperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4698]¹H-NMR (DMSO-d₆) δ: 1.32 (6H, br), 2.60-2.70 (2H, m), 3.40-3.60(2H, m), 3.80-4.10 (1H, br), 4.50-4.90 (1H, br), 7.01 (1H, s), 7.30-7.35(1H, m), 7.45-7.55 (3H, m), 7.75-7.85 (5H, m), 8.27 (2H, d, J=6.8 Hz),12.44 (1H, s).

[4699] Elementary analysis for C₂₆H₂₅ClN₄O₄S.0.5H₂O

[4700] Calculated: C, 58.48; H, 4.91; Cl, 6.64; N, 10.49; S, 6.00.

[4701] Found: C, 58.68; H, 5.02; Cl, 6.72; N, 10.51; S, 6.04.

Example A-1134-[4-[[4-[(5-Chlorobenzo[b]furan-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4702]¹H-NMR (CDCl₃) δ: 3.20-3.50 (4H, br), 3.50-4.05 (4H, br), 7.34(1H, s), 7.45-7.53 (6H, m), 7.62 (2H, d, J=7.8 Hz), 7.69 (1H, s).

[4703] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[4704] Elementary analysis for C₂₄H₂₀ClN₃O₅S.0.25H₂O

[4705] Calculated: C, 57.37; H, 4.11; Cl, 7.06; N, 8.36; S, 6.38.

[4706] Found: C, 57.31; H, 4.30; Cl, 7.17; N, 8.22; S, 6.40.

Example A-1144-[4-[[4-[(6-Chlorobenzo[b]furan-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4707]¹H-NMR (CDCl₃) δ: 3.20-3.50 (4H, br), 3.50-4.10 (4H, br),3.65-3.85 (2H, br), 7.35-7.41 (2H, br), 7.46-7.55 (5H, br), 7.58-7.67(5H, m), 8.27 (2H, d, J=5.9 Hz).

[4708] HRMS (FAB) m/z: 498.0901 (M+H)⁺ (calcd for C₂₄H₂₁ClN₃O₅S498.0890).

Example A-1154-[4-[[4-[(5-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4709]¹H-NMR (DMSO-d₆) δ: 3.02-3.90 (8H, m), 7.59 (2H, d, J=8.3 Hz),7.64 (1H, d, J=2.0 Hz), 8.01-8.05 (3H, m), 8.18 (1H, d, J=2.0 Hz), 8.20(1H, d, J=8.8 Hz), 8.31 (2H, d, J=6.3 Hz), 8.94 (2H, d, J=6.3 Hz).

[4710] MS (FAB) m/z: 514 [(M+H)⁺, Cl³⁵], 516 [(M+H)⁺, Cl³⁷].

[4711] Elementary analysis for C₂₄H₂₀ClN₃O₃S₂.0.8H₂O

[4712] Calculated: C, 54.55; H, 4.12; Cl, 6.71; N, 7.95; S, 12.14.

[4713] Found: C, 54.66; H, 4.09; Cl, 6.95; N, 7.77; S, 11.87.

Example A-1164-[4-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4714]¹H-NMR (DMSO-d₆) δ: 3.16-3.88 (8H, m), 7.48 (2H, d, J=8.3 Hz),7.58 (1H, dd, J=8.8, 2.0 Hz), 7.77 (1H, d, J=7.3 Hz), 7.79 (1H, s), 7.81(2H, d, J=8.8 Hz), 8.08 (2H, d, J=8.8 Hz), 8.27 (1H, d, J=7.3 Hz), 8.33(1H, s).

[4715] MS (FAB) m/z: 514 [(M+H)⁺, Cl³⁵], 516 [(M+H)⁺, Cl³⁷].

[4716] Elementary analysis for C₂₄H₂₀ClN₃O₄S₂.1.2H₂O

[4717] Calculated: C, 53.82; H, 4.22; Cl, 6.62; N, 7.84; S, 11.97.

[4718] Found: C, 53.66; H, 4.22; Cl, 6.81; N, 7.61; S, 11.72.

Example A-1172-(4-([4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4719]¹H-NMR (DMSO-d₆) δ: 3.06-3.94 (8H, m), 7.38-7.42 (2H, m), 7.46(2H, d, J=8.3 Hz), 7.54-7.63 (2H, m), 7.86 (2H, d, J=8.3 Hz), 8.07 (2H,t, J=4.4 Hz), 8.27-8.34 (2H, m).

[4720] MS (FAB) m/z: 514 [(M+H)⁺, Cl³⁵], 516 [(M+H)⁺, Cl³⁷].

[4721] Elementary analysis for C₂₄H₂₀ClN₃O₄S₂.0.5H₂O.0.1CH₂Cl₂

[4722] Calculated: C, 54.56; H, 4.01; Cl, 7.99; N, 7.89; S, 12.04.

[4723] Found: C, 54.93; H, 3.95; Cl, 7.90; N, 7.74; S, 11.71.

Example A-1184-[4-[[4-[(5-Chlorobenzothiazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4724]¹H-NMR (CDCl₃) δ: 3.40-4.00 (8H, m), 7.50 (2H, d, J=7.3 Hz), 7.51(2H, d, J=8.3 Hz), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.63 (2H, d, J=8.3 Hz),7.93 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=2.0 Hz), 8.27 (2H, d, J=7.3 Hz).

[4725] MS (FAB) m/z: 515 [(M+H)⁺, Cl³⁵], 517 [(M+H)⁺, Cl³⁷].

[4726] Elementary analysis for C₂₃H₁₉ClN₄O₄S₂.0.1H₂O

[4727] Calculated: C, 53.45; H, 3.74; Cl, 6.86; N, 10.84; S, 12.41.

[4728] Found: C, 53.19; H, 3.72; Cl, 7.09; N, 10.70; S, 12.29.

Example A-1194-[4-[[4-[(6-Chlorobenzothiazol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4729]¹H-NMR (DMSO-d₆) δ: 3.30-3.85 (8H, m), 7.50 (2H, d, J=8.3 Hz),7.77 (1H, dd, J=8.8, 2.0 Hz), 7.80 (2H, d, J=7.3 Hz), 7.83 (2H, d, J=8.3Hz), 8.28 (2H, d, J=7.3 Hz), 8.29 (1H, d, J=8.8 Hz), 8.50 (1H, d, J=2.0Hz).

[4730] MS (FAB) m/z: 515 [(M+H)⁺, Cl³⁵], 517 [(M+H)⁺, Cl³⁷].

[4731] Elementary analysis for C₂₃H₁₉ClN₄O₄S₂

[4732] Calculated: C, 53.64; H, 3.72; Cl, 6.88; N, 10.88; S, 12.45.

[4733] Found: C, 53.64; H, 3.99; Cl, 6.63; N, 10.90; S, 12.30.

Example A-1204-[4-[[4-[(5-Ethynylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4734]¹H-NMR (CDCl₃) δ: 2.80-3.90 (8H, br), 4.05 (1H, s), 7.06 (1H, brs), 7.39 (1H, d, J=8.8 Hz), 7.43-7.52 (3H, m), 7.77-7.86 (4H, m), 7.89(1H, br s), 8.27 (2H, d, J=6.8 Hz), 12.43 (1H, br s).

[4735] MS (FAB) m/z: 487 (M+H)⁺.

[4736] Elementary analysis for C₂₆H₂₂N₄O₄S.H₂O

[4737] Calculated: C, 61.89; H, 4.79; N, 11.10; S, 6.36.

[4738] Found: C, 62.00; H, 4.67; N, 11.08; S, 6.35.

Example A-1211-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]piperazine

[4739] In the same manner as in Example A-4, a reaction was effected,whereby the title compound was obtained.

[4740]¹H-NMR (DMSO-d₆) δ: 3.06 (2H, br), 3.14 (2H, br), 3.45-3.85 (4H,m), 7.74 (1H, d, J=8.3 Hz), 7.83 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.3Hz), 8.25-8.29 (2H, m), 8.31 (2H, d, J=5.9 Hz), 8.52 (1H, br s), 8.89(2H, d, J=5.9 Hz), 9.02 (2H, s).

[4741] MS (FAB) m/z: 494 [(M+H)⁺, Cl³⁵], 496 [(M+H)⁺, Cl³⁷].

[4742] Elementary analysis for C₂₄H₂₀ClN₅O₃S.HCl.H₂O

[4743] Calculated: C, 52.56; H, 4.23; Cl, 12.93; N, 12.77; S, 5.85.

[4744] Found: C, 52.47; H, 4.20; Cl, 13.09; N, 12.60; S, 5.98.

Example A-1224-[5-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-Oxide

[4745] In the same manner as in Example A-6, a reaction was effected,whereby the title compound was obtained.

[4746]¹H-NMR (CDCl₃) δ: 3.05-3.30 (4H, br), 3.55-4.00 (4H, br), 7.61(1H, dd, J=8.3 and 2.0 Hz), 7.76 (1H, dd, J=8.8 and 2.0 Hz), 7.91-7.97(3H, m), 8.25-8.29 (2H, m), 8.31-8.35 (3H, m), 8.77 (2H, s).

[4747] MS (FAB) m/z: 510 [(M+H)⁺, Cl³⁵], 512 [(M+H)⁺, Cl³⁷].

[4748] Elementary analysis for C₂₄H₂₀ClN₅O₄S.0.8H₂O

[4749] Calculated: C, 54.97; H, 4.15; Cl, 6.76; N, 13.36; S, 6.11.

[4750] Found: C, 54.99; H, 4.08; Cl, 6.75; N, 13.24; S, 6.20.

Example A-1231-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[4751] In the same manner as in Example A-105, the title compound wasobtained.

[4752]¹H-NMR (DMSO-d₆) δ: 2.94 (2H, br s), 3.13 (2H, br s), 3.37 (2H, brs), 3.80 (2H, br s), 7.74 (1H, dd, J=8.8, 2.4 Hz), 7.83 (1H, dd, J=8.8,2.0 Hz), 8.05-8.18 (2H, br), 8.19 (1H, d, J=8.8 Hz), 8.25-8.32 (2H, m),8.52 (1H, br s), 8.82-8.91 (2H, br), 9.33-9.38 (2H, m).

[4753] MS (FAB) m/z: 494 [(M+H)⁺, Cl³⁵], 496 [(M+H)⁺, Cl³⁷].

[4754] Elementary analysis for C₂₄H₂₀ClN₅O₃S.0.95HCl.0.5H₂O

[4755] Calculated: C, 53.62; H, 4.12; Cl, 12.86, N, 13.03; S, 5.96.

[4756] Found: C, 53.50; H, 4.09; Cl, 12.76; N, 12.87; S, 5.91.

Example A-1244-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[4757] In the same manner as in Example A-6, the title compound wasobtained.

[4758]¹H-NMR (CDCl₃) δ: 3.14-3.17 (2H, m), 3.25-3.28 (2H, m), 3.55-3.58(2H, m), 3.94-3.98 (2H, m), 7.50 (2H, d, J=7.3 Hz), 7.60 (1H, dd, J=8.8,2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.91-7.96 (3H, m), 8.30-8.35 (3H,m), 8.98 (2H, s).

[4759] MS (FAB) m/z: 510 [(M+H)⁺, Cl³⁵], 512 [(M+H)⁺, Cl³⁷].

[4760] Elementary analysis for C₂₄H₂₀ClN₅O₄S.0.6H₂O

[4761] Calculated: C, 55.35; H, 4.10; Cl, 6.81; N, 13.45; S, 6.16.

[4762] Found: C, 55.01; H, 4.01; Cl, 7.00; N, 13.28; S, 6.28.

Example A-1254-[4-[[4-[(6-Bromonaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4763] In the same manner as in Example A-1, the title compound wasobtained using 4-[4-[(piperazin-1-yl)carbonyl]phenyl]pyridine N-oxidehydrochloride and (6-bromonaphthalen-2-yl)sulfonyl chloride as startingmaterials.

[4764]¹H-NMR (CDCl₃) δ: 2.80-3.40 (4H, br), 3.40-4.05 (4H, br), 7.43(2H, d, J=7.8 Hz), 7.47 (2H, d, J=7.1 Hz), 7.58 (2H, d, J=7.8 Hz),7.70-7.78 (2H, m), 7.85 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz), 8.13(1H, s), 8.26 (2H, d, J=7.1 Hz), 8.30 (1H, s).

[4765] MS (FAB) m/z: 552 [(M+H)⁺, Br⁷⁹], 554 [(M+H)⁺, B⁸¹].

[4766] Elementary analysis for C₂₆H₂₂BrN₃O₄S.0.5H₂O

[4767] Calculated: C, 55.62; H, 4.13; N, 7.48; Br, 14.23; S, 5.71.

[4768] Found: C, 55.36; H, 3.89; N, 7.41; Br, 14.20; S, 5.59.

Example A-1261-[(6-Bromonaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4769] In the same manner as in Example A-1, a reaction was effected,whereby the title compound was obtained.

[4770]¹H-NMR (CDCl₃) δ: 2.80-3.40 (4H, br), 3.40-4.10 (4H, br), 7.43(2H, d, J=8.3 Hz), 7.47 (2H, d, J=5.6 Hz), 7.63 (2H, d, J=8.3 Hz),7.72-7.78 (2H, m), 7.86 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz), 8.13(1H, d, J=1.5 Hz), 8.30 (1H, s), 8.68 (2H, d, J=5.6 Hz).

[4771] MS (FAB) m/z: 536 [(M+H)⁺, Br⁷⁹], 538 [(M+H)⁺, Br⁸¹].

[4772] Elementary analysis for C₂₆H₂₂BrN₃O₃S.0.5H₂O

[4773] Calculated: C, 57.25; H, 4.25; N, 7.70; Br, 14.65; S, 5.88.

[4774] Found: C, 57.51; H, 3.96; N, 7.67; Br, 14.76; S, 6.01.

Example A-1271-[(6-Ethynylnaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[4775] To a solution of1-[(6-bromonaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine(310 mg) and triphenylphosphine (455 mg) in tetrahydrofuran (1.0 ml),triethylamine (3.0 ml), N,N-dimethylformamide (1.0 ml),trimethylsilylacetylene (130 ml) and palladium acetate (13.0 mg) wereadded, followed by heating under reflux for 2 hours. After the reactionmixture was allowed to cool down to room temperature, dichloromethane(15 ml) and water (30 ml) were added to separate the organic layer. Theorganic layer thus obtained was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column(dichloromethane:acetone=3:1), whereby colorless amorphous was obtained.The resulting product was dissolved in methanol (25 ml), followed by theaddition of tetrahydrofuran (5.0 ml) and potassium carbonate (300 mg).The resulting mixture was stirred for 30 minutes. Dichloromethane (30ml) and water (50 ml) were added to the reaction mixture to separate theorganic layer. The organic layer thus obtained was dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue was purified by chromatography on a silica gelcolumn (dichloromethane:acetone=4:1), followed by pulverization andwashing in a mixed solvent of dichloromethane, acetone and water,whereby the title compound (210 mg, 75%) was obtained.

[4776]¹H-NMR (CDCl₃) δ: 2.80-4.10 (8H, br), 7.43 (2H, d, J=8.3 Hz), 7.47(2H, d, J=6.4 Hz), 7.67 (2H, d, J=8.3 Hz), 7.68 (1H, dd, J=8.8, 1.5 Hz),7.75 (1H, dd, J=8.3, 1.5 Hz), 7.93 (1H, d, J=8.3 Hz), 7.97 (1H, d, J=8.8Hz), 8.11 (1H, s), 8.30 (1H, s), 8.68 (2H, d, J=6.4 Hz).

[4777] MS (FAB) m/z: 482 (M+H)⁺.

[4778] Elementary analysis for C₂₈H₂₃N₃O₃S.0.4H₂O

[4779] Calculated: C, 68.81; H., 4.91; N, 8.60; S, 6.56.

[4780] Found: C, 68.96; H, 4.91; N, 8.47; S, 6.52.

Example A-1284-[4-[[4-[(6-Ethynylnaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4781] In the same manner as in Example A-6, the title compound wasobtained.

[4782]¹H-NMR (CDCl₃) δ: 2.95-4.00 (8H, br), 7.42 (2H, d, J=8.3 Hz), 7.46(2H, d, J=6.8 Hz), 7.58 (2H, d, J=8.3 Hz), 7.68 (1H, dd, J=8.8, 1.5 Hz),7.75 (1H, dd, J=8.3, 1.5 Hz), 7.92 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=8.3Hz), 8.10 (1H, s), 8.25 (2H, d, J=6.8 Hz), 8.30 (1H, s).

[4783] MS (FAB) m/z: 498 [(M+H)⁺].

[4784] Elementary analysis for C₂₈H₂₃N₃O₄S.H₂O

[4785] Calculated: C, 65.23; H, 4.89; N, 8.15; S, 6.22.

[4786] Found: C, 65.41H, 5.14; N, 8.19; S, 6.11.

Example A-1292-Carbamoylmethyl-4-[(5-chloro-1-phenylsulfonyl-5-chloroindol-2-ylsulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[4787] In the same manner as in Example A-7 or Example A-1, a reactionwas effected, whereby the title compound was obtained.

[4788]¹H-NMR (CDCl₃) δ: 2.44-3.28 (4H, m), 3.50-4.14 (2H, m), 4.45-4.78(1H, m), 5.58-5.79 (1H, m), 7.44-7.65 (13H, m), 7.69 (2H, d, J=8.3 Hz),8.05 (2H, d, J=8.3 Hz), 8.13-8.17 (1H, m), 8.69 (2H, d, J=5.9 Hz)

[4789] MS (FAB) m/z: 678 [(M+H)⁺, Cl³⁵], 680 [(M+H)⁺, Cl³⁷].

Example A-1302-Carbamoylmethyl-4-[(5-chloroindol-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[4790] In the same manner as in Example A-99, the title compound wasobtained.

[4791]¹H-NMR (DMSO-d₆) δ: 2.55-2.80 (2H, m), 3.00-4.56 (6H, m),5.05-5.17 (1H, m), 6.90-7.05 (2H, m), 7.34 (1H, dd, J=8.8, 2.2 Hz),7.40-7.63 (4H, m), 7.79 (1H, m), 7.99 (1H, m), 8.24 (2H, br), 8.90 (1H,m), 12.43 (1H, s).

[4792] MS (FAB) m/z: 538 [(M+H)⁺, Cl³⁵], 540 [(M+H)⁺, Cl³⁷].

[4793] Elementary analysis for C₂₆H₂₄ClN₅O₄S.1.2HCl.2.5H₂O

[4794] Calculated: C, 49.82; H, 4.86; Cl, 12.44; N, 11.17; S, 5.12.

[4795] Found: C, 50.14; H, 5.07; Cl, 12.54; N, 10.80; S, 5.18.

Example A-1311-[(5-Chloroindol-2-yl)sulfonyl]-4-[[2-(pyridin-4-yl)pyrimidin-5-yl]carbonyl]piperazine

[4796] In the same manner as in Example A-4, a reaction was effected,whereby the title compound was obtained.

[4797]¹H-NMR (DMSO-d₆) δ: 3.08 (2H, br), 3.18 (2H, br), 3.52 (2H, br),3.77 (2H, br), 7.04 (1H, d, J=1.5 Hz), 7.34 (1H, dd, J=8.8, 2.0 Hz),7.50 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=2.0 Hz), 8.48-8.53 (2H, m),8.91-8.95 (2H, m), 9.07 (2H, s), 12.46 (1H, br s).

[4798] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

[4799] Elementary analysis for C₂₂H₁₉ClN₆O₃S.HCl.1.3H₂O.0.2EtOH

[4800] Calculated: C, 48.74; H, 4.35; Cl, 12.84; N, 15.22; S, 5.81.

[4801] Found: C, 48.87; H, 4.38; Cl, 12.82; N, 15.02; S, 5.86.

Example A-1321-[(6-Chlorobenzothiophen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[4802] In the same manner as in Example A-105, the title compound wasobtained.

[4803]¹H-NMR (DMSO-d₆) δ: 3.03-3.06 (2H, m), 3.20-3.23 (2H, m),3.41-3.44 (2H, m), 3.83-3.86 (2H, m), 7.61 (1H, dd, J=8.8, 2.0 Hz), 8.10(1H, d, J=8.8 Hz), 8.13 (1H, s), 8.30-8.40 (3H, m), 8.90-9.02 (2H, br),9.40-9.46 (2H, m).

[4804] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

[4805] Elementary analysis for C₂₂H₁₉ClN₅O₃S.HCl.0.7H₂O

[4806] Calculated: C, 48.13; H, 3.74; Cl, 12.91; N, 12.75; S, 11.68.

[4807] Found: C, 47.95; H, 3.78; Cl, 13.13; N, 12.65; S, 11.53.

Example A-1334-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[4808] In the same manner as in Example A-6, a reaction was effected,whereby the title compound was obtained.

[4809]¹H-NMR (CDCl₃) δ: 3.24 (2H, br), 3.34 (2H, br), 3.60 (2H, br),3.98 (2H, br), 7.47 (1H, dd, J=8.8, 2.0 Hz), 7.52 (2H, d, J=7.3 Hz),7.79 (1H, s), 7.83 (1H, d, J=8.8 Hz), 7.88 (1H, br s), 8.33 (2H, d,J=7.3 Hz), 9.00 (2H, s).

[4810] MS (FAB) m/z: 516 [(M+H)⁺, Cl³⁵], 518 [(M+H)⁺, Cl³⁷].

[4811] Elementary analysis for C₂₂H₁₈ClN₅O₄S.0.4H₂O

[4812] Calculated: C, 50.50; H, 3.62; Cl, 6.78; N, 13.39; S, 12.26.

[4813] Found: C, 50.24; H, 3.62; Cl, 7.14; N, 13.19; S, 12.04.

Example A-1344-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[4814] In the same manner as in Example A-6, a reaction was effected,whereby the title compound was obtained.

[4815]¹H-NMR (DMSO-d₆) δ: 2.95 (2H, br), 3.15 (2H, br), 3.37 (2H, br),3.79 (2H, br), 7.05 (1H, s), 7.34 (1H, dd, J=8.8, 1.5 Hz), 7.51 (1H, d,J=8.8 Hz), 7.80 (1H, d, J=1.5 Hz), 7.95 (2H, d, J=7.3 Hz), 8.37 (2H, d,J=7.3 Hz), 9.28 (2H, s), 12.47 (1H, s).

[4816] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

[4817] Elementary analysis for C₂₂H₁₉ClN₆O₄S.0.5H₂O.0.2EtOH

[4818] Calculated: C, 52.02; H, 4.13; Cl, 6.86; N, 16.25; S, 6.20.

[4819] Found: C, 52.03; H, 3.99; Cl, 7.18; N, 15.99; S, 6.16.

Example A-1354-[5-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-2-yl]pyridineN-oxide

[4820] In the same manner as in Example A-6, a reaction was effected,whereby the title compound was obtained.

[4821]¹H-NMR (DMSO-d₆) δ: 3.09 (2H, br), 3.16 (2H, br), 3.53 (2H, br),3.75 (2H, br), 7.03 (1H, s), 7.32 (1H, dd, J=8.8, 2.0 Hz), 7.50 (1H, d,J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 8.27 (2H, d, J=7.3 Hz), 8.34 (2H, d,J=7.3 Hz), 8.95 (2H, s), 12.42 (1H, br s).

[4822] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

[4823] Elementary analysis for C₂₂H₁₉ClN₆O₄S.H₂O

[4824] Calculated: C, 51.11; H, 4.09; Cl, 6.86; N, 16.26; S, 6.20.

[4825] Found: C, 51.29; H, 4.34; Cl, 6.80; N, 15.90; S, 6.08.

Example A-1361-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[4826] In the same manner as in Example A-105, the title compound wasobtained.

[4827]¹H-NMR (DMSO-d₆) δ: 3.20 (2H, t, J=4.9 Hz), 3.62-3.78 (2H, m),3.45-3.60 (2H, m), 3.78 (2H, t, J=4.9 Hz), 4.63 (2H, s), 4.64 (2H, s),7.35 (1H, d, J=8.3 Hz), 7.38 (1H, d, J=8.3 Hz), 7.42 (1H, s), 8.22 (2H,d, J=5.4 Hz), 8.92 (2H, d, J=5.4 Hz), 9.44 (2H, s).

[4828] MS (FAB) m/z: 485 [(M+H)⁺, Cl³⁵], 487 [(M+H)⁺, Cl³⁷].

[4829] Elementary analysis for C₂₂H₂₁ClN₆O₃S.HCl.1.8H₂O

[4830] Calculated: C, 47.71; H, 4.66; Cl, 12.80; N, 15.17; S, 5.79.

[4831] Found: C, 48.01; H, 4.39; Cl, 13.19; N, 14.74; S, 573.

[4832] In the same manner as in Example A-4, the compounds shown inExamples A-137 and A-138 were synthesized.

Example A-1371-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]piperazine

[4833]¹H-NMR (DMSO-d₆) δ: 3.01 (2H, br), 3.14 (2H, br), 3.62 (2H, br),3.81 (2H, br), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.84 (1H, dd, J=8.8, 2.0Hz), 8.19 (1H, d, J=8.8 Hz), 8.25-8.31 (2H, m), 8.46 (2H, d, J=5.4 Hz),8.52 (1H, br s), 8.91 (3H, m), 9.47 (1H, s).

[4834] MS (FAB) m/z: 494 [(M+H)⁺, Cl³⁵], 496 [(M+H)⁺, Cl³⁷].

[4835] Elementary analysis for C₂₄H₂₀ClN₅O₃S.HCl.H₂O.0.2AcOEt

[4836] Calculated: C, 52.62; H, 4.38; Cl, 12.53; N, 12.37; S, 5.66.

[4837] Found: C, 52.47; H, 4.51; Cl, 12.87; N, 12.09; S, 5.68.

Example A-1381-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrazin-2-yl]carbonyl]piperazine

[4838]¹H-NMR (DMSO-d₆) δ: 3.04 (2H, br), 3.18 (2H, br), 3.63 (2H, br),3.81 (2H, br), 7.05 (1H, s), 7.33 (1H, dd, J=8.8, 2.0 Hz), 7.50 (1H, d,J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 8.11 (2H, d, J=6.4 Hz), 8.77 (2H, d,J=6.4 Hz), 8.93 (1H, d, J=1.5 Hz), 9.34 (1H, d, J=1.5 Hz), 12.43 (1H, brs).

[4839] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

[4840] Elementary analysis for C₂₂H₁₉ClN₆O₃S.H₂O

[4841] Calculated C; 52.75; H, 4.23; Cl, 7.08; N, 16.78; S, 6.40.

[4842] Found: C, 52.78; H, 4.27; Cl, 7.17; N, 16.67; S, 6.37.

[4843] In the same manner as in Example A-6, reaction was effected,whereby the compounds shown in Examples A-139 and A-140 weresynthesized.

Example A-1394-[5-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrazin-2-yl]pyridineN-Oxide

[4844]¹H-NMR (CDCl₃) δ: 3.19 (2H, br), 3.26 (2H, br), 3.88 (2H, br),3.94 (2H, br), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.78 (1H, dd, J=8.8, 2.0Hz), 7.91-7.95 (3H, m), 7.98 (2H, d, J=7.3 Hz), 8.30 (2H, d, J=7.3 Hz),8.32 (1H, d, J=2.0 Hz), 8.90 (1H, d, J=1.5 Hz), 8.99 (1H, d, J=1.5 Hz).

[4845] MS (FAB) m/z: 510 [(M+H)⁺, Cl³⁵], 512 [(M+H)⁺, Cl³⁷].

[4846] Elementary analysis for C₂₄H₂₀ClN₅O₄S.1.1H₂O

[4847] Calculated: C, 54.41; H, 4.22; Cl, 6.69; N, 13.22; S, 6.05.

[4848] Found: C, 54.27; H, 4.61; Cl, 6.99; N, 13.28; S, 6.12.

Example A-1404-[5-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrazin-2-yl]pyridineN-Oxide

[4849]¹H-NMR (DMSO-d₆) δ: 3.03 (2H, br), 3.17 (2H, br), 3.63 (2H, br),3.80 (2H, br), 7.04 (1H, s), 7.33 (1H, dd, J=8.8, 2.0 Hz), 7.50 (1H, d,J=8.8 Hz), 7.80 (1H, d, J=2.0 Hz), 8.19 (2H, d, J=7.3 Hz), 8.37 (2H, d,J=7.3 Hz), 8.87 (1H, d, J=1.5 Hz), 9.31 (1H, d, J=1.5 Hz), 12.45 (1H, brs).

[4850] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

[4851] Elementary analysis for C₂₂H₁₉ClN₆O₄S.H₂O

[4852] Calculated: C, 51.11; H, 4.09; Cl, 6.86; N, 16.26; S, 6.20.

[4853] Found: C, 50.92; H, 4.05; Cl, 6.96; N, 15.88; S, 6.10.

Example A-1411-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(3-methylpyridin-4-yl)benzoyl]piperazineHydrochloride

[4854] In the same manner as in Example A-4, a reaction was effected,whereby the title compound was obtained.

[4855]¹H-NMR (DMSO-d₆) δ: 2.36 (3H, s), 2.95-3.30 (4H, br), 3.35-3.90(4H, br), 7.50 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 7.71 (1H, d,J=5.4 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz),8.18 (1H, d, J=8.8 Hz), 8.24-8.30 (2H, m), 8.50 (1H, br s), 8.72 (1H, d,J=5.4 Hz), 8.80 (1H, s).

[4856] MS (FAB) m/z: 506 [(M+H)⁺, Cl³⁵], 508 [(M+H)⁺, Cl³⁷].

[4857] Elementary analysis for C₂₇H₂₄ClN₃O₃S.0.8HCl.1.5H₂O

[4858] Calculated: C, 57.68; H, 4.98; Cl, 11.35; N, 7.48; S, 5.70.

[4859] Found: C, 57.50; H, 5.06; Cl, 11.35; N, 7.28; S, 5.95.

Example A-1424-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-3-methylpyridineN-Oxide

[4860] In the same manner as in Example A-6, a reaction was effected,whereby the title compound was obtained.

[4861]¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 3.14 (4H, br), 3.68 (2H, br), 3.85(2H, br), 7.09 (1H, d, J=6.8 Hz), 7.32 (2H, d, J=8.3 Hz), 7.41 (2H, d,J=8.3 Hz), 7.60 (1H, dd, J=8.8, 2.0 Hz), 7.77 (1H, dd, J=8.8, 2.0 Hz),7.90-7.96 (3H, m), 8.11 (1H, dd, J=6.4, 1.5 Hz), 8.15 (1H, br s), 8.31(1H, br s).

[4862] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁷].

[4863] Elementary analysis for C₂₇H₂₄ClN₃O₄S.0.1H₂O

[4864] Calculated: C, 61.92; H, 4.66; Cl, 6.77; N, 8.02; S, 6.12.

[4865] Found: C, 61.76; H, 4.72; Cl, 7.04; N, 7.76; S, 6.30.

Example A-1431-(4-Amidinobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[4866] In the same manner as in Example A-4, a reaction was effected,whereby the title compound was obtained.

[4867]¹H-NMR (DMSO-d₆) δ: 3.03 (2H, br s), 3.13 (2H, br s), 3.30 (2H, brs), 3.73 (2H, br s), 7.56 (2H, d, J=8.3 Hz), 7.73 (1H, dd, J=8.8, 2.0Hz), 7.78-7.85 (3H, m), 8.18 (1H, d, J=8.3 Hz), 8.25-8.30 (2H, m), 8.50(1H, s), 9.10 (2H, br s), 9.38 (2H, br s).

[4868] MS (FAB) m/z: 457 [(M+H)⁺, Cl³⁵], 459 [(M+H)⁺, Cl³⁷].

Example A-1441-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(4,5-dihydroimidazol-2-yl)benzoyl]piperazine

[4869]¹H-NMR (DMSO-d₆) δ: 3.04 (2H, br s), 3.13 (2H, br s), 3.37 (2H, brs), 3.74 (2H, br s), 4.00 (4H, s), 7.60 (2H, d, J=8.3 Hz), 7.73 (1H, dd,J=8.8, 2.0 Hz), 7.83 (1H, d, J=8.8 Hz), 8.11 (2H, d, J=8.3 Hz), 8.19(1H, d, J=8.8 Hz), 8.26 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=8.8 Hz), 8.50(1H, s), 11.00 (2H, br s).

[4870] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

Example A-1451-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-[2-(N-tert-butoxycarbonylamino)pyridin-4-yl]benzoyl]piperazine

[4871] In the same manner as in Example A-4, the title compound wasobtained.

[4872]¹H-NMR (CDCl₃) δ: 1.54 (9H, s), 3.00-3.30 (4H, m), 3.40-4.10 (4H,m), 7.14 (1H, dd, J=5.4, 1.5 Hz), 7.38 (2H, d, J=8.3 Hz), 7.53 (1H, brs), 7.60 (1H, dd, J=8.8, 2.0 Hz), 7.67 (2H, d, J=8.3 Hz), 7.77 (1H, dd,J=8.3, 1.5 Hz), 7.91-7.98 (3H, m), 8.18 (1H, d, J=1.5 Hz), 8.29 (1H, d,J=5.4 Hz), 8.32 (1H, s).

Example A-1461-[4-(2-Aminopyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[4873] In the same manner as in Example A-7, the title compound wasobtained.

[4874]¹H-NMR (DMSO-d₆) δ: 2.95-3.25 (4H, m), 3.30-3.93 (4H, m),7.14-7.23 (2H, m), 7.51 (2H, d, J=8.3 Hz), 7.66-7.75 (1H, m), 7.76 (2H,d, J=8.8 Hz), 7.82 (1H, m), 8.03 (1H, d, J=6.8 Hz), 8.05-8.12 (2H, m),8.13-8.30 (3H, m), 8.50 (1H, s), 13.60 (1H, br).

[4875] MS (FAB) m/z: 507 [(M+H)⁺, Cl³⁵], 509 [(M+H)⁺, Cl³⁷].

[4876] Elementary analysis for C₂₆H₂₃ClN₄O₃S.HCl.3.6H₂O

[4877] Calculated: C, 51.34; H, 5.17; Cl, 11.66; N, 9.21; S, 5.27.

[4878] Found: C, 51.07; H, 5.24; Cl, 11.85; N, 9.10; S, 5.75.

Example A-1472-tert-Butoxycarbonylamino-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4879] In the same manner as in Example A-6, the title compound wasobtained.

[4880]¹H-NMR (CDCl₃) δ: 1.55 (9H, s), 2.95-3.35 (4H, br), 3.50-4.00 (4H,m), 7.11 (1H, dd, J=6.8, 2.5 Hz), 7.40 (2H, d, J=8.3 Hz), 7.60 (1H, dd,J=8.8, 2.0 Hz), 7.64 (2H, d, J=8.3 Hz), 7.77 (1H, dd, J=8.8, 2.0 Hz),7.91-7.98 (3H, m), 8.25 (1H, d, J=6.8 Hz), 8.31 (1H, d, J=2.0 Hz), 8.42(1H, d, J=2.5 Hz), 9.28 (1H, s).

[4881] MS (FAB) m/z: 623 [(M+H)⁺, Cl³⁵], 625 [(M+H)⁺, Cl³⁷].

[4882] Elementary analysis for C₃₁H₃₁ClN₄O₆S.0.1H₂O

[4883] Calculated: C, 59.58; H, 5.03; Cl, 5.67; N, 8.97; S, 5.13.

[4884] Found: C, 59.43; H, 5.04; Cl, 5.95; N, 8.89; S, 5.17.

Example A-1482-Amino-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4885] In the same manner as in Example A-7, the title compound wasobtained.

[4886]¹H-NMR (DMSO-d₆) δ: 2.95-3.25 (4H, br), 3.30-3.90 (4H, m), 7.14(1H, dd, J=6.8, 2.0 Hz), 7.28 (1H, d, J=2.0 Hz), 7.49 (2H, d, J=8.3 Hz),7.70-7.78 (3H, m), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.16 (2H, br), 8.18(1H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.32 (1H, d, J=6.8 Hz), 8.50 (1H,br s).

[4887] MS (FAB) m/z: 523 [(M+H)⁺, Cl³⁵], 525 [(M+H)⁺, Cl³⁷].

[4888] Elementary analysis for C₂₆H₂₃ClN₄O₄S.HCl.1.5H₂O

[4889] Calculated: C, 53.25; H, 4.64; Cl, 12.09; N, 9.55; S, 5.47.

[4890] Found: C, 53.21; H, 4.67; Cl, 11.96; N, 9.53; S, 5.61.

Example A-1494-[5-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyridin-2-yl]pyridineN-Oxide

[4891] In the same manner as in Example A-6, the title compound wasobtained.

[4892]¹H-NMR (CDCl₃) δ: 3.00-3.40 (4H, br s), 3.50-4.05 (4H, m), 7.61(1H, dd, J=8.8, 2.0 Hz), 7.73-7.83 (3H, m), 7.90-7.97 (5H, m), 8.27 (2H,d, J=7.3 Hz), 8.31 (1H, br s), 8.63 (1H, m).

[4893] MS (FAB) m/z: 509 [(M+H)⁺, Cl³⁵], 511 [(M+H)⁺, Cl³⁷].

[4894] Elementary analysis for C₂₅H₂₁ClN₄O₄S.0.5H₂O

[4895] Calculated: C, 57.97; H, 4.28; Cl, 6.84; N, 10.82; S, 6.19.

[4896] Found: C, 57.99; H, 4.51; Cl, 6.99; N, 10.54; S, 6.53.

Example A-1501-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[1-oxo-6-(1-oxopyridin-4-yl)pyridin-3-yl]carbonyl]piperazine

[4897] In the same manner as in Example A-6, the title compound wasobtained.

[4898]¹H-NMR (CDCl₃) δ: 3.15 (4H, br s), 3.50-4.00 (4H, m), 7.20-7.30(1H, m), 7.52 (1H, d, J=8.3 Hz), 7.61 (1H, dd, J=8.8, 2.0 Hz), 7.76 (1H,dd, J=8.8, 2.0 Hz), 7.89 (2H, d, J=7.3 Hz), 7.91-7.97 (3H, m), 8.21 (1H,d, J=1.5 Hz), 8.26 (2H, d, J=7.3 Hz), 8.31 (1H, br s).

[4899] MS (FAB) m/z: 525 [(M+H)⁺, Cl³⁵], 527 [(M+H)⁺, Cl³⁷].

[4900] Elementary analysis for C₂₅H₂₁ClN₄O₅S.0.1H₂O

[4901] Calculated: C, 57.00; H, 4.06; Cl, 6.73; N, 10.64; S, 6.09.

[4902] Found C, 57.03; H, 4.23; Cl, 6.82; N, 10.34; S, 6.15.

Example A-1511-[4-(2-Acetoxymethylpyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4903] In acetic anhydride (25 ml),4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-oxide (900 mg) was dissolved, followed by heating under reflux for 15minutes. Ethanol (25 ml) was added to the reaction mixture and theresulting mixture was heated under reflux for further 1 hour. To thereaction mixture, dichloromethane and an aqueous solution of sodiumbicarbonate were added to separate the organic layer. The organic layerthus obtained was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to remove the solvent. The residue was purifiedby chromatography on a silica gel column (dichloromethane˜1.5%methanol—dichloromethane), followed by crystallization from ethanol. Thecrystals were dissolved in dichloromethane and the resulting solutionwas made acidic by the addition of hydrochloric acid in ethanol. Theresulting acidic mixture was concentrated, whereby the title compound(842 mg, 87%, pale yellow powder) was obtained.

[4904]¹H-NMR (DMSO-d₆) δ: 2.12 (3H, s), 3.06 (4H, br), 3.30-3.80 (4H,br), 5.23 (2H, s), 7.48 (2H, d, J=8.3 Hz), 7.72 (1H, dd, J=8.8, 2.4 Hz),7.78 (1H, d, J=5.4 Hz), 7.79-7.87 (4H, m), 8.17 (1H, d, J=8.8 Hz),8.23-8.29 (2H, m), 8.49 (1H, br s), 8.67 (1H, d, J=5.4 Hz).

[4905] MS (FAB) m/z: 564 [(M+H)⁺, Cl³⁵], 566 [(M+H)⁺, Cl³⁷].

[4906] Elementary analysis for C₂₉H₂₆ClN₃O₅S.0.4HCl.0.7H₂O

[4907] Calculated: C, 58.91; H, 4.74; Cl, 8.39; N, 7.11; S, 5.42.

[4908] Found: C, 58.86; H, 4.69; Cl, 8.29; N, 6.99; S, 5.41.

Example A-1521-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine

[4909] In the same manner as in Example A-3, the title compound wasobtained.

[4910]¹H-NMR (DMSO-d₆) δ: 3.08 (4H, br), 3.47 (2H, br), 3.71 (2H, br),4.66 (2H, s), 7.49 (2H, d, J=8.3 Hz), 7.64 (1H, d, J=5.4 Hz), 7.73 (1H,dd, J=8.8, 2.0 Hz), 7.78-7.85 (4H, m), 8.18 (1H, d, J=8.8 Hz), 8.23-8.30(2H, m), 8.50 (1H, br s), 8.58 (1H, d, J=5.4 Hz).

[4911] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁷].

[4912] Elementary analysis for C₂₇H₂₄ClN₃O₄S.0.25HCl.1.2H₂O

[4913] Calculated: C, 58.67; H, 4.86; Cl, 8.02; N, 7.60; S, 5.80.

[4914] Found: C, 58.73; H, 4.77; Cl, 7.94; N, 7.39; S, 5.82.

Example A-1532-Acetoxymethyl-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4915] In the same manner as in Example A-6, the title compound wasobtained.

[4916]¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 3.14 (4H, br), 3.30-4.10 (4H, br),5.42 (2H, s), 7.40-7.46 (3H, m), 7.54-7.64 (4H, m), 7.76 (1H, d, J=7.3Hz), 7.90-7.97 (3H, m), 8.29 (1H, d, J=6.4 Hz), 8.31 (1H, br s).

[4917] MS (FAB) m/z: 580 [(M+H)⁺, Cl³⁵], 582 [(M+H)⁺, Cl³⁷].

[4918] Elementary analysis for C₂₉H₂₆ClN₃O₆S.0.3H₂O

[4919] Calculated: C, 59.49; H, 4.58; Cl, 6.06; N, 7.18; S, 5.48.

[4920] Found: C, 59.33; H, 4.63; Cl, 6.18; N, 7.26; S, 5.49.

Example A-1544-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-hydroxymethylpyridineN-Oxide

[4921] In the same manner as in Example A-3, the title compound wasobtained.

[4922]¹H-NMR (CDCl₃) δ: 3.06 (4H, br), 3.30-3.90 (4H, br), 4.63 (2H, d,J=5.4 Hz), 5.66 (1H, t, J=5.4 Hz), 7.46 (2H, d, J=8.3 Hz), 7.70 (1H, dd,J=6.8, 2.9 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.78 (2H, d, J=8.3 Hz),7.80-7.84 (2H, m), 8.18 (1H, d, J=8.8 Hz), 8.25-8.32 (3H, m), 8.50 (1H,br s).

[4923] MS (FAB) m/z: 538 [(M+H)⁺, Cl³⁵], 540 [(M+H)⁺, Cl³⁷].

[4924] Elementary analysis for C₂₇H₂₄ClN₃O₅S.0.4H₂O

[4925] Calculated: C, 59.48; H, 4.58; Cl, 6.50; N, 7.71; S, 5.88.

[4926] Found: C, 59.60; H, 4.56; Cl, 6.50; N, 7.52; S, 5.92.

Example A-1551-[4-(2-Aminomethylpyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4927] At room temperature,1-[4-(2-azidomethylpyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(159 mg) was dissolved in tetrahydrofuran (5 ml), followed by theaddition of water (0.5 ml) and triphenylphosphine (114 mg). Theresulting mixture was stirred for 18 hours. The residue obtained bydistilling off the solvent under reduced pressure was purified bychromatography on a silica gel column (10% methanol—dichloromethane),followed by dissolution in dichloromethane. To the resulting solution,1N hydrochloric acid in ethanol and water were added. The resultingmixture was then concentrated. The crystals were collected by filtrationand washed with ethyl acetate, whereby the title compound (53 mg, 30%)was obtained.

[4928]¹H-NMR (DMSO-d₆) δ: 3.07 (4H, br), 3.30-4.20 (4H, m), 4.24 (1H, d,J=5.8 Hz), 4.27 (1H, d, J=5.8 Hz), 7.51 (2H, d, J=8.3 Hz), 7.71-7.78(2H, m), 7.80-7.87 (3H, m), 7.89 (1H, br s), 8.19 (1H, d, J=8.8 Hz),8.25-8.30 (2H, m), 8.42 (2H, br s), 8.50 (1H, br s), 8.69 (1H, d, J=5.4Hz).

[4929] MS (FAB) m/z: 521 [(M+H)⁺, Cl³⁵], 523 [(M+H)⁺, Cl³⁷].

[4930] Elementary analysis for C₂₇H₂₅ClN₄O₃S.1.5HCl.2.1H₂O

[4931] Calculated: C, 52.85; H, 5.04; Cl, 14.45; N, 9.13; S, 5.23.

[4932] Found: C, 52.69; H, 4.93; Cl, 14.60; N, 9.21; S, 5.25.

Example A-1561-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-[2-(dimethylaminomethyl)pyridin-4-yl]benzoyl]piperazineHydrochloride

[4933] In the same manner as in Referential Example 178, thecorresponding brome compound was obtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine(300 mg). To the resulting compound, dimethylamine hydrochloride (469mg) and potassium carbonate (795 mg) were added, followed by stirringfor 24 hours. The solvent was then distilled off under reduced pressure.Ethyl acetate and water were added to the residue to separate theorganic layer. The organic layer thus obtained was dried over anhydroussodium sulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(3 to 5% methanol—dichloromethane). Hydrochloric acid in ethanol wasadded and the resulting mixture was concentrated. Ethyl acetate wasadded to the concentrate. The colorless powder thus obtained wascollected by filtration and dried, whereby the title compound (74 mg,21%) was obtained.

[4934]¹H-NMR (DMSO-d₆) δ: 2.82 (6H, s), 3.07 (4H, br), 3.30-3.90 (4H,m), 4.50 (2H, br s), 7.51 (2H, d, J=7.8 Hz), 7.73 (1H, dd, J=8.8, 2.0Hz), 7.79-7.85 (2H, m), 7.86 (2H, d, J=7.8 Hz), 8.00 (1H, br s), 8.19(1H, d, J=8.8 Hz), 8.25-8.30 (2H, m), 8.50 (1H, br s), 8.73 (1H, d,J=4.9 Hz).

[4935] MS (FAB) m/z: 549 [(M+H)⁺, Cl³⁵], 551 [(M+H)⁺, Cl³⁷].

[4936] Elementary analysis for C₂₉H₂₉ClN₄O₃S.1.1HCl.2H₂O

[4937] Calculated: C, 55.71; H, 5.50; Cl, 11.91; N, 8.96; S, 5.13.

[4938] Found: C, 55.61; H, 5.49; Cl, 11.89; N, 9.18; S, 5.27.

Example A-1571-[4-[2-[(tert-Butoxycarbonylamino)methyl]pyridin-4-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[4939] In the same manner as in Referential Example 10, a reaction waseffected, whereby the title compound was obtained.

[4940]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 3.13 (4H, br), 3.40-4.00 (4H, m),4.50 (2H, d, J=5.4 Hz), 5.57 (1H, br s), 7.35 (1H, dd, J=5.4, 1.5 Hz),7.41 (2H, d, J=8.3 Hz), 7.44 (1H, br s), 7.57-7.65 (3H, m), 7.76 (1H,dd, J=8.3, 1.5 Hz), 7.90-7.97 (3H, m), 8.31 (1H, d, J=1.5 Hz), 8.59 (1H,d, J=5.4 Hz).

[4941] MS (FAB) m/z: 621 [(M+H)⁺, Cl³⁵], 623 [(M+H)⁺, Cl³⁷].

Example A-1582-[(tert-Butoxycarbonylamino)methyl]-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4942] In the same manner as in Example A-6, the title compound wasobtained.

[4943]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 3.13 (4H, br), 3.40-4.00 (4H, m),4.52 (2H, d, J=6.3 Hz), 5.86 (1H, br s), 7.39-7.44 (3H, m), 7.56-7.63(4H, m), 7.77 (1H, dd, J=8.8, 2.0 Hz), 7.91-7.97 (3H, m), 8.27 (1H, d,J=6.8 Hz), 8.31 (1H, d, J=2.0 Hz).

[4944] MS (FAB) m/z: 637 [(M+H)⁺, Cl³⁵], 639 [(M+H)⁺, Cl³⁷].

[4945] Elementary analysis for C₃₂H₃₃ClN₄O₆S.0.7H₂O

[4946] Calculated: C, 59.15; H, 5.34; Cl, 5.46; N, 8.62; S, 4.94.

[4947] Found: C, 58.92; H, 5.41; Cl, 5.56; N, 8.52; S, 5.05.

Example A-1592-Aminomethyl-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4948] In the same manner as in Example A-7, the title compound wasobtained.

[4949]¹H-NMR (DMSO-d₆) δ: 3.07 (4H, br), 3.35-3.95 (4H, m), 4.24 (2H, d,J=5.4 Hz), 7.49 (2H, d, J=8.3 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz),7.80-7.87 (3H, m), 7.89 (1H, dd, J=6.8, 2.4 Hz), 8.17-8.22 (2H, m),8.25-8.30 (2H, m), 8.45 (1H, d, J=6.8 Hz), 8.51 (1H, br s), 8.71 (3H, brs).

[4950] MS (FAB) m/z: 537 [(M+H)⁺, Cl³⁵], 539 [(M+H)⁺, Cl³⁷].

[4951] Elementary analysis for C₂₇H₂₅ClN₄O₄S.1.7HCl.H₂O

[4952] Calculated: C, 52.56; H, 4.69; Cl, 15.51; N, 9.08; S, 5.20.

[4953] Found: C, 52.69; H, 4.85; Cl, 15.51; N, 8.90; S, 5.13.

Example A-1601-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-cyanopyridin-4-yl)benzoyl]piperazine

[4954] In dichloromethane (100 ml),4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-oxide (1.67 g) was dissolved, followed by the addition oftrimethylsilycynanide (0.42 ml) and dimethylcarbamoyl chloride (0.30ml). The resulting mixture was stirred at room temperature for 24 hours.An aqueous solution of sodium bicarbonate and dichloromethane were addedto the reaction mixture to separate the organic layer. The organic layerthus obtained was dried over anhydrous sodium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column (1%methanol—dichloromethane), whereby the title compound (1.44 g, 84%) wasobtained.

[4955]¹H-NMR (CDCl₃) δ: 3.14 (4H, br s), 3.49 (2H, br s), 3.89 (2H, brs), 7.47 (2H, d, J=8.3 Hz), 7.55-7.72 (4H, m), 7.76 (1H, dd, J=8.8, 1.5Hz), 7.87 (1H, s), 7.90-8.04 (3H, m), 8.31 (1H, br s), 8.77 (1H, d,J=4.9 Hz).

[4956] MS (FAB) m/z: 517 [(M+H)⁺, Cl³⁵], 519 [(M+H)⁺, Cl³⁷].

[4957] Elementary analysis for C₂₇H₂₁ClN₄O₃S.0.05CH₂Cl₂

[4958] Calculated: C, 62.33; H, 4.08; Cl, 7.48; N, 10.75; S, 6.15.

[4959] Found: C, 62.16; H, 4.20; Cl, 7.65; N, 10.69; S, 6.04.

Example A-1614-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-cyanopyridineN-Oxide

[4960] In the same manner as in Example A-6, the title compound wasobtained.

[4961]¹H-NMR (CDCl₃) δ: 3.13 (4H, br s), 3.60 (2H, br s), 3.87 (2H, brs), 7.46 (2H, d, J=8.3 Hz), 7.54-7.65 (4H, m), 7.76 (1H, dd, J=8.3, 10.5Hz), 7.83 (1H, d, J=2.9 Hz), 7.90-7.97 (3H, m), 8.28-8.33 (2H, m).

[4962] MS (FAB) m/z: 533 [(M+H)⁺, Cl³⁵], 535 [(M+H)⁺, Cl³⁷].

[4963] Elementary analysis for C₂₇H₂₁ClN₄O₄S

[4964] Calculated: C, 60.84; H, 3.97; Cl, 6.65; N, 10.51; S, 6.02.

[4965] Found: C, 60.76; H, 4.04; Cl, 6.64; N, 10.39; S, 6.05.

Example A-1621-[4-[2-[2-(tert-Butoxycarbonylamino)ethyl]pyridin-4-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[4966] In a similar manner to Example A-3 and Example A-4, a reactionwas effected using methyl4-[2-[2-(tert-butoxycarbonylamino)ethyl]pyridin-4-yl]benzoate as astarting material, whereby the title compound was obtained.

[4967]¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 3.04 (2H, t, J=6.4 Hz), 3.12 (4H,br), 3.45-4.00 (6H, m), 5.11 (1H, br s), 7.31 (1H, dd, J=5.4, 2.0 Hz),7.35 (1H, br s), 7.41 (2H, d, J=8.3 Hz), 7.58-7.65 (3H, m), 7.77 (1H,dd, J=8.3, 1.5 Hz), 7.90-7.97 (3H, m), 8.31 (1H, s), 8.59 (1H, d, J=5.4Hz).

[4968] MS (FAB) m/z: 635 [(M+H)⁺, Cl³⁵], 637 [(M+H)⁺, Cl³⁷].

[4969] Elementary analysis for C₃₃H₃₅ClN₄O₅S

[4970] Calculated: C, 62.40; H, 5.55; N, 8.82.

[4971] Found: C, 62.78; H, 5.93; N, 8.51.

Example A-1634-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-[2-(tert-butoxycarbonylamino)ethyl]pyridineN-Oxide

[4972] In the same manner as in Example A-6, the title compound wasobtained.

[4973]¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 3.00-3.30 (6H, m), 3.50-4.00 (6H,m), 5.28 (1H, br s), 7.37 (1H, dd, J=6.8, 2.9 Hz), 7.41 (2H, d, J=8.3Hz), 7.51 (1H, br s), 7.56-7.63 (3H, m), 7.77 (1H, dd, J=8.3, 1.5 Hz),7.91-7.97 (3H, m), 8.28 (1H, d, J=6.8 Hz), 8.31 (1H, d, J=1.5 Hz).

[4974] MS (FAB) m/z: 651 [(M+H)⁺, Cl³⁵], 653 [(M+H)⁺, Cl³⁷].

[4975] Elementary analysis for C₃₃H₃₅ClN₄O₆S.0.8H₂O

[4976] Calculated: C, 59.55; H, 5.54; N, 8.42.

[4977] Found: C, 59.75; H, 5.61; N, 8.07.

Example A-1642-(2-Aminoethyl)-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[4978] In the same manner as in Example A-7, the title compound wasobtained using4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-[2-(tert-butoxycarbonylamino)ethyl]pyridineN-oxide as a starting material.

[4979]¹H-NMR (DMSO-d₆) δ: 2.95-3.30 (6H, m), 3.30-3.90 (6H, m), 7.47(2H, d, J=8.3 Hz), 7.71-8.10 (8H, m), 8.19 (1H, d, J=8.8 Hz), 8.26-8.30(2H, m), 8.37 (1H, d, J=6.8 Hz), 8.51 (1H, br s).

[4980] MS (FAB) m/z: 551 [(M+H)⁺, Cl³⁵], 553 [(M+H)⁺, Cl³⁷].

[4981] Elementary analysis for C₂₈H₂₇ClN₄O₄S.1.1HCl.1.6H₂O

[4982] Calculated: C, 54.24; H, 5.09; Cl, 12.01; N, 9.04; S, 5.17.

[4983] Found: C, 54.40; H, 5.36; Cl, 11.90; N, 8.97; S, 5.27.

Example A-1654-[(6-Chloronaphthalen-2-yl)sulfonyl]-5-methoxycarbonyl-1-[4-(pyridin-4-yl)benzoyl]-1,2,3,4-tetrahydropyrazine

[4984] In N,N-dimethylformamide (1 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine(60 mg) and p-nitrophenyl 4-(pyridin-4-yl)benzoate (52 mg) weredissolved, followed by the addition of sodium hydride (60% in oil, 7.20mg) under ice cooling. The resulting mixture was stirred for 1 hour.Water and ethyl acetate were added to the reaction mixture to separatethe organic layer. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (ethylacetate:hexane=2:1), followed by dissolution in ethanol. To theresulting solution, 1N aqueous hydrochloric acid in ethanol was addedand the resulting mixture was concentrated, whereby the title compound(58 mg, 60%) was obtained as pale yellow powder.

[4985]¹H-NMR (CDCl₃) δ: 3.51 (2H, s), 3.79 (3H, s), 3.99 (2H, s), 7.60(1H, dd, J=8.8, 2.0 Hz), 7.68 (1H, br), 7.76 (2H, d, J=7.8 Hz), 7.90(2H, d, J=7.8 Hz), 7.92-7.99 (3H, m), 8.12 (2H, d, J=5.4 Hz), 8.16 (1H,dd, J=8.8, 1.5 Hz), 8.58 (1H, br s), 8.93 (2H, d, J=5.4 Hz).

[4986] MS (FAB) m/z: 548 [(M+H)⁺, Cl³⁵], 550 [(M+H)⁺, Cl³⁷].

[4987] Elementary analysis for C₂₈H₂₂ClN₃O₅S.0.8HCl.1.3H₂O

[4988] Calculated: C, 55.99; H, 4.26; Cl, 10.63; N, 7.00; S, 5.34.

[4989] Found: C, 55.96; H, 4.31; Cl, 10.43; N, 6.94; S, 5.56.

Example A-1661-[(6-Chloronaphthalen-2-yl)sulfonyl]-5-methoxycarbonyl-4-[4-(pyridin-4-yl)benzoyl-1,2,3,4-tetrahydropyrazine

[4990] In the same manner as in Referential Example 7, the titlecompound was obtained using4-(4-bromobenzoyl)-1-[(6-chloronaphthalen-2-yl)sulfonyl]-5-methoxycarbonyl-1,2,3,4-tetrahydropyrazineas a starting material.

[4991]¹H-NMR (DMSO-d₆) δ: 3.10-3.90 (7H, m), 7.43 (1H, s), 7.66 (2H, d,J=8.3 Hz), 7.78 (1H, dd, J=8.8, 2.0 Hz), 7.96 (1H, dd, J=8.8, 2.0 Hz),8.02 (2H, d, J=8.3 Hz), 8.20-8.38 (5H, m), 8.74 (1H, br s), 8.94 (2H, d,J=6.3 Hz).

[4992] MS (FAB) m/z: 548 [(M+H)⁺, Cl³⁵], 550 [(M+H)⁺, Cl³⁷].

[4993] Elementary analysis for C₂₈H₂₂ClN₃O₅S.0.8HCl.0.5H₂O

[4994] Calculated: C, 57.37; H, 4.09; Cl, 10.89; N, 7.17; S, 5.47.

[4995] Found: C, 57.24; H, 4.15; Cl, 10.88; N, 6.97; S, 5.29.

Example A-167cis-1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-cyanopyridin-4-yl)benzoyl]-2,6-dimethylpiperazine

[4996] In the same manner as in Example A-160, the title compound wasobtained.

[4997]¹H-NMR (CDCl₃) δ: 1.40-1.60 (6H, m), 2.40-2.60 (2H, m), 3.40-3.90(3H, m), 4.40-4.90 (1H, br), 7.43 (2H, d, J=8.3 Hz), 7.60 (1H, dd,J=8.8, 2.0 Hz), 7.64 (2H, d, J=8.3 Hz), 7.69 (1H, dd, J=5.4, 2.0 Hz),7.76 (1H, dd, J=8.8, 1.5 Hz), 7.88 (1H, d, J=2.0 Hz), 7.90-7.95 (3H, m),8.31 (1H, d, J=1.5 Hz), 8.78 (1H, d, J=5.4 Hz).

[4998] MS (FAB) m/z: 545 [(M+H)⁺, Cl³⁵], 547 [(M+H)⁺, Cl³⁷].

[4999] Elementary analysis for C₂₉H₂₅ClN₄O₃S

[5000] Calculated: C, 63.90; H, 4.62; Cl, 6.50; N, 10.28; S, 5.88.

[5001] Found: C, 63.87; H, 4.98; Cl, 6.33; N, 9.96; S, 5.75.

Example A-1684-[4-cis-4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,6-dimethylpiperazin-1-yl]carbonyl]phenyl]-2-cyanopyridineN-Oxide

[5002] In the same manner as in Example A-6, the title compound wasobtained.

[5003]¹H-NMR (CDCl₃) δ: 1.42-1.55 (6H, m), 2.43-2.60 (2H, m), 3.40-3.90(3H, m), 4.40-4.90 (1H, br), 7.42 (2H, d, J=8.3 Hz), 7.58 (2H, d, J=8.3Hz), 7.60-7.65 (2H, m), 7.76 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, d, J=2.9Hz), 7.90-7.95 (3H, m), 8.29-8.32 (2H, m).

[5004] MS (FAB) m/z: 561 [(M+H)⁺, Cl³⁵], 563 [(M+H)⁺, Cl³⁷].

[5005] Elementary analysis for C₂₉H₂₅ClN₄O₄S.0.3H₂O

[5006] Calculated: C, 61.49; H, 4.56; Cl, 6.26; N, 9.89; S, 5.66.

[5007] Found: C, 61.47; H, 4.63; Cl, 6.13; N, 9.72; S, 5.73.

Example A-1691-[4-[(3-Aminomethyl)phenyl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5008] In the same manner as in Example A-4 and Example A-7, a reactionwas effected, whereby the title compound was obtained.

[5009]¹H-NMR (DMSO-d₆) δ: 3.07 (4H, br), 3.51 (2H, br), 3.69 (2H, br),4.09 (2H, s), 7.45 (2H, d, J=8.3 Hz), 7.47-7.55 (2H, m), 7.66-7.76 (4H,m), 7.80-7.87 (2H, m), 8.19 (2H, d, J=8.8 Hz), 8.25-8.42 (4H, m), 8.51(1H, br s).

[5010] MS (FAB) m/z: 520 [(M+H)⁺, Cl³⁵], 522 [(M+H)⁺, Cl³⁷].

[5011] Elementary analysis for C₂₈H₂₆ClN₃O₃S.HCl

[5012] Calculated: C, 60.34; H, 4.89 Cl, 12.74; N, 7.55; S, 5.76.

[5013] Found: C, 60.15; H, 4.89; Cl, 12.44; N, 7.52; S, 5.80.

Example A-1701-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2,5-dihydro-5-oxo-3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazine

[5014] In the same manner as in Example A-4, the title compound wasobtained.

[5015]¹H-NMR (DMSO-d₆) δ: 2.94 (2H, br s), 3.07 (2H, br s), 3.52 (2H, brs), 3.73 (2H, br s), 7.74 (1H, dd, J=8.8, 2.4 Hz), 7.84 (1H, dd, J=8.8,2.0 Hz), 7.99 (2H, d, J=6.3 Hz), 8.20 (1H, d, J=8.8 Hz), 8.26-8.31 (2H,m), 8.53 (1H, br s), 8.87 (2H, d, J=6.3 Hz)

[5016] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

[5017] Elementary analysis for C₂₃H₁₉ClN₆O₄S.0.6HCl.1.5H₂O

[5018] Calculated: C, 49.34; H, 4.07; Cl, 10.13; N, 15.01; S, 5.73.

[5019] Found: C, 49.25; H, 4.01; Cl, 10.12; N, 15.07; S, 5.59.

Example A-171trans-2,6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5020] In the same manner as in Example A-105, the title compound wasobtained as colorless amorphous powder by usingtrans-2,6-bis(methoxycarbonylmethyl)-1-(4-bromobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5021]¹H-NMR (DMSO-d₆) δ: 2.50-2.65 (2H, m), 3.70-3.80 (2H, m),3.30-3.40 (4H, m), 3.46 (6H, s), 4.23 (2H, br), 7.60 (2H, d, J=8.3 Hz),7.74 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=8.3 Hz), 8.03 (2H, d, J=8.3 Hz),8.15-8.40 (4H, m), 8.53 (1H, s), 8.90-9.00 (2H, m).

[5022] MS (FAB) m/z: 636 [(M+H)⁺, Cl³⁵], 638 [(M+H)⁺, Cl³⁷].

[5023] Elementary analysis for C₃₂H₃₀ClN₃O₇S.HCl.2.6H₂O

[5024] Calculated: C, 53.42; H, 5.07; Cl, 9.86; N, 5.84; S, 4.46.

[5025] Found: C, 53.21; H, 4.75; Cl, 9.91; N, 5.80; S, 4.54.

Example A-172cis-2,6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5026] In the same manner as in Example A-171, the title compound wasobtained.

[5027]¹H-NMR (DMSO-d₆) δ: 2.70-3.00 (6H, m), 3.40-3.80 (2H, m), 3.51(3H, s), 3.68 (3H, s), 4.13 (1H, br), 4.97 (1H, br), 7.58 (2H, d, J=7.8Hz), 7.70-7.75 (1H, m), 7.80-7.90 (1H, m), 8.03 (2H, d, J=8.3 Hz), 8.19(1H, d, J=8.8 Hz), 8.25-8.35 (4H, m), 8.55 (1H, s), 8.90-8.95 (2H, m).

[5028] MS (FAB) m/z: 636 [(M+H)⁺, Cl³⁵], 638 [(M+H)⁺, Cl³⁷].

[5029] Elementary analysis for C₃₂H₃₀ClN₃O₇S.HCl.0.3H₂O

[5030] Calculated: C, 56.69; H, 4.70; Cl, 10.46; N, 6.20; S, 4.73.

[5031] Found: C, 56.72; H, 4.66; Cl, 10.31; N, 6.03; S, 4.71.

Example A-173cis-2,6-Bis(carbamoylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5032] In the same manner as in Example A-35, the title compound wasobtained usingcis-2,6-bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazineas a starting material.

[5033]¹H-NMR (DMSO-d₆) δ: 2.30-2.60 (10H, m), 2.80-2.90 (2H, m),3.45-3.55 (1H, m), 3.75-3.85 (1H, m), 4.10-4.20 (1H, m), 4.95-5.05 (1H,m), 6.85 (1H, br s), 7.03 (1H, br s), 7.40 (1H, br s), 7.45 (1H, br s),7.56 (2H, d, J=8.3 Hz), 7.70-7.75 (1H, m), 7.80-7.85 (1H, m), 8.02 (2H,d, J=8.3 Hz), 8.18 (1H, d, J=8.8 Hz), 8.25-8.40 (4H, m), 8.52 (1H, s),8.95 (2H, d, J=6.8 Hz).

[5034] MS (FAB) m/z: 606 [(M+H)⁺, Cl³⁵], 608 [(M+H)⁺, Cl³⁷].

[5035] Elementary analysis for C₃₀H₂₈ClN₅O₅S.1.2HCl.2.8H₂O

[5036] Calculated: C, 51.45; H, 5.01; N, 11.14; Cl, 10.00; S, 4.58.

[5037] Found: C, 51.52; H, 5.30; N, 11.33; Cl, 10.01; S, 4.72.

Example A-1744-[4-[[cis-2,6-Bis(carbamoylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[5038] In the same manner as in Example A-6, the title compound wasobtained.

[5039]¹H-NMR (DMSO-d₆) δ: 2.30-2.60 (4H, m), 2.75-2.90 (2H, m),3.45-3.55 (1H, m), 3.75-3.85 (1H, m), 4.10-4.20 (1H, m), 4.90-5.00 (1H,m), 6.86 (1H, br), 7.02 (1H, br), 7.30-7.50 (4H, m), 7.70-7.85 (6H, m),8.18 (1H, d, J=8.8 Hz), 8.25-8.35 (4H, m), 8.52 (1H, s).

[5040] MS (FAB) m/z: 622 [(M+H)⁺, Cl³⁵], 624 [(M+H)⁺, Cl³⁷].

[5041] Elementary analysis for C₃₀H₂₈ClN₅O₆S.1.6H₂O

[5042] Calculated: C, 55.36; H, 4.83; Cl, 5.45; N, 10.76; S, 4.93.

[5043] Found: C, 55.05; H, 4.77; Cl, 5.77; N, 10.51; S, 4.90.

Example A-1754-[4-[[cis-2,6-Bis(ethoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[5044] In the same manner as in Example A-6, the title compound wasobtained.

[5045]¹H-NMR (CDCl₃) δ: 2.85-2.95 (4H, m), 3.20-3.40 (4H, m), 3.63 (6H,s), 4.25-4.35 (2H, m), 7.45-7.50 (4H, m), 7.55-7.65 (3H, m), 7.70-7.80(1H, m), 7.90-7.95 (3H, m), 8.25-8.35 (3H, m).

[5046] MS (FAB) m/z: 652 [(M+H)⁺, Cl³⁵], 654 [(M+H)⁺, Cl³⁷].

[5047] Elementary analysis for C₃₂H₃₀ClN₃O₈S.2.3H₂O

[5048] Calculated: C, 55.42; H, 5.03; Cl, 5.11; N, 6.06; S, 4.62.

[5049] Found: C, 55.50; H, 4.93; Cl, 5.12; N, 5.89; S, 4.54.

Example A-176trans-2,6-Bis(carbamoylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5050] In the same manner as in Example A-105, the title compound wasobtained usingtrans-2,6-bis(carbamoylmethyl)-1-(4-bromobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5051]¹H-NMR (DMSO-d₆) δ: 2.50-2.60 (4H, m), 3.20-3.30 (4H, m),4.15-4.25 (2H, m), 6.87 (2H, br s), 7.40 (2H, br s), 7.62 (2H, d, J=8.8Hz), 7.72 (1H, d, J=8.3 Hz), 7.82 (1H, d, J=8.8 Hz), 8.02 (2H, d, J=8.3Hz), 8.16 (1H, d, J=8.8 Hz), 8.20-8.40 (4H, m), 8.51 (1H, s), 8.90-9.00(2H, m).

[5052] MS (FAB) m/z: 606 [(M+H)⁺, Cl³⁵], 608 [(M+H)⁺, Cl³⁷].

[5053] Elementary analysis for C₃₀H₂₈ClN₅O₅S.1.2HCl.3H₂O

[5054] Calculated: C, 51.19; H, 5.04; Cl, 11.08; N, 9.95; S, 4.56.

[5055] Found: C, 51.10; H, 4.97; Cl, 11.17; N, 9.71; S, 4.64.

Example A-1774-[4-[[trans-2,6-Bis(carbamoylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[5056] In the same manner as in Example A-6, the title compound wasobtained.

[5057]¹H-NMR (DMSO-d₆) δ: 2.55-2.65 (2H, m), 2.65-2.80 (2H, m),3.20-3.60 (4H, m), 4.25-4.35 (2H, m), 4.90-5.00 (1H, m), 6.98 (2H, br),7.48 (2H, br), 7.55-7.65 (2H, m), 7.80-8.00 (6H, m), 8.20-8.40 (5H, m),8.60 (1H, s)

[5058] MS (FAB) m/z: 622 [(M+H)⁺, Cl³⁵], 624 [(M+H)⁺, Cl³⁷].

Example A-178trans-2,6-bis(carboxymethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5059] In the same manner as in Example A-3, the title compound wasobtained.

[5060]¹H-NMR (DMSO-d₆) δ: 2.50-2.75 (4H, m), 3.25-3.45 (4H, m),4.15-4.25 (2H, m), 7.52 (2H, d, J=8.3 Hz) 7.70-7.75 (3H, m), 7.80-7.85(3H, m), 8.16 (1H, d, J=8.8 Hz), 8.20-8.30 (2H, m), 8.51 (1H, s),8.60-8.70 (2H, m), 12.32 (2H, s).

[5061] MS (FAB) m/z: 608 [(M+H)⁺, Cl³⁵], 610 [(M+H)⁺, Cl³⁷].

[5062] Elementary analysis for C₃₀H₂₆ClN₃O₇S.0.2HCl.0.5H₂O

[5063] Calculated: C, 57.71; H, 4.39; Cl, 6.81; N, 6.73; S, 5.14.

[5064] Found: C, 57.78; H, 4.35; Cl, 6.73; N, 6.68; S, 5.11.

Example A-179trans-2,6-Bis(2-hydroxyethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5065] In tetrahydrofuran (40 ml),trans-2,6-bis(carboxymethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine(269 mg) was suspended, followed by the addition ofN,N-diisopropylethylamine (480 μl) and1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate(672 mg) under ice cooling. The resulting mixture was stirred for 3.5hours at room temperature. Under ice cooling, sodium borohydride (297mg) was added and the resulting mixture was stirred for 15 hours at roomtemperature. The reaction mixture was ice cooled and added with waterand ethyl acetate to separate the organic layer. The organic layer thusobtained was washed with aqueous NaCl solution, dried over anhydroussodium sulfate. The residue obtained by distilling off the solvent underreduced pressure was purified by chromatography on a silica gel column(4% methanol—dichloromethane), followed by dissolution intetrahydrofuran. Saturated hydrochloride in methanol was added to theresulting solution and the resulting mixture was concentrated todryness. Ethyl acetate was then added to the residue to crystallize thesame, whereby the title compound was obtained.

[5066]¹H-NMR (DMSO-d₆) δ: 1.60-1.80 (2H, m), 1.80-1.95 (2H, m),3.20-3.40 (6H, m), 3.95-4.05 (2H, m), 7.59 (2H, d, J=8.3 Hz), 7.70-7.75(3H, m), 7.80-7.90 (31H, m), 7.99 (2H, d, J=8.3 Hz), 8.17 (1H, d, J=8.8Hz), 8.20-8.30 (4H, m), 8.54 (1H, s), 8.85-8.95 (2H, m).

[5067] HRMS (FAB) m/z: 580.1633 (M+H)⁺ (calcd for C₃₀H₃₀ClN₃O₅S580.1673).

Example A-1801-[(5-Chloroindol-2-yl)sulfonyl]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine

[5068] In the same manner as in Example A-4, the title compound wasobtained.

[5069]¹H-NMR (DMSO-d₆) δ: 2.74 (3H, s), 2.99-3.81 (8H, br), 7.71 (1H,s), 7.33 (1H, dd, J=8.8, 2.0 Hz), 7.51 (1H, d, J=8.8 Hz), 7.58 (2H, d,J=8.3 Hz), 7.79 (1H, d, J=2.0 Hz), 8.00 (2H, d, J=8.3 Hz), 8.77-8.84(1H, m), 8.79 (1H, d, J=6.3 Hz), 12.50 (1H, s).

[5070] MS (FAB) m/z: 495 [(M+H)⁺, Cl³⁵], 497 [(M+H)⁺, Cl³⁷].

[5071] Elementary analysis for C₂₅H₂₃ClN₄O₃S.0.9HCl.H₂O

[5072] Calculated: C, 55.01; H, 4.78; Cl, 12.34; N, 10.26; S, 5.87.

[5073] Found: C, 54.99; H, 5.01; Cl, 12.12; N, 10.03; S, 5.88.

Example A-1814-[4-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridineN-Oxide

[5074] In the same manner as in Example A-6, the title compound wasobtained.

[5075] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

[5076]¹H-NMR (DMSO-d₆) δ: 2.95-3.18 (4H, br), 3.37-3.81 (4H, br), 7.03(1H, s), 7.34 (1H, dd, J=8.8, 2.0 Hz), 7.47 (2H, d, J=8.3 Hz), 7.51 (1H,d, J=8.8 Hz), 7.66 (1H, dd, J=6.8, 2.9 Hz), 7.79 (1H, s), 7.80 (2H, d,J=8.3 Hz), 7.91 (1H, d, J=2.9 Hz), 8.30 (1H, d, J=6.8 Hz), 12.42 (1H, s)

[5077] Elementary analysis for C₂₅H₂₃ClN₄O₄S.0.8H₂O

[5078] Calculated: C, 57.15; H, 4.72; Cl, 6.75; N, 10.66; S, 6.10.

[5079] Found: C, 57.22; H, 4.64; Cl, 7.04; N, 10.42; S, 6.17.

Example A-1821-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5080] At room temperature,1-[(5-bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(500 mg) and (pyridin-2-yl)tributyltin (418 mg) were dissolved inN,N-dimethylformamide (10 ml). To the reaction mixture was addedtetrakis(triphenylphosphine)palladium(0) (69 mg), followed by stirringat 100° C. for 9 hours. After cooling to room temperature, ethyl acetateand ammonia solution were added. The resulting mixture was separated byethyl acetate and water. The organic layer was dried over anhydroussodium sulfate. The filtrate was concentrated and the residue waspurified by chromatography on a silica gel column (4% methanol—methylenechloride). The resulting fraction was added with ethanol, followed byconcentration. Diethyl ether was then added to the concentrate.Colorless powder thus precipitated was collected by filtration anddried, whereby the free form (254 mg) of the title compound wasobtained. The resulting free form was dissolved in methylene chloride,followed by the addition of 1N hydrochloric acid (in ethanol) to makethe solution acidic. After concentration, ethyl acetate and diethylether were added, followed by concentration. Colorless powder thusprecipitated was collected by filtration and dried, whereby the titlecompound was obtained.

[5081]¹H-NMR (DMSO-d₆) δ: 2.90-2.98 (2H, m), 3.10-3.15 (2H, m),3.30-3.41 (2H, m), 3.75-3.85 (2H, m), 7.05 (1H, d, J=2.0 Hz), 7.35 (1H,dd, J=2.0 and 8.8 Hz), 7.47-7.53 (2H, m), 7.80 (1H, d, J=2.0 Hz), 8.00(1H, dt, J=2.0 and 8.3 Hz), 8.17 (1H, d, J=8.3 Hz), 8.76 (1H, d, J=4.4Hz), 9.47 (2H, s), 12.47 (1H, s).

[5082] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

Example A-1832-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5083] In the same manner as in Example A-6, the title compound wasobtained.

[5084]¹H-NMR (CDCl₃) δ: 3.10-3.20 (2H, m), 3.20-3.30 (2H, m), 3.50-3.60(2H, m), 3.85-3.95 (2H, m), 6.97 (1H, s), 7.30-7.52 (5H, m), 7.68 (1H,s), 8.39 (1H, d, J=5.9 Hz), 9.28 (2H, s), 9.50 (1H, s).

[5085] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

Example A-1841-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5086] In the same manner as in Example A-182, the title compound wasobtained.

[5087]¹H-NMR (DMSO-d₆) δ: 3.01-3.10 (2H, m), 3.17-3.26 (2H, m),3.39-3.47 (2H, m), 3.79-3.87 (2H, m), 7.52 (1H, dd, J=7.3 and 4.9 Hz),7.61 (1H, d, J=8.8 Hz), 8.01 (1H, dt, J=1.5 and 7.3 Hz), 8.10 (1H, d,J=8.8 Hz), 8.12 (1H, s), 8.18 (1H, d, J=7.3 Hz), 8.35 (1H, s), 8.76 (1H,d, J=4.9 Hz), 9.48 (2H, s).

[5088] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

Example A-1852-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5089] In the same manner as in Example A-6, the title compound wasobtained.

[5090]¹H-NMR (CDCl₃) δ: 3.24 (2H, t, J=4.9 Hz), 3.33 (2H, t, J=4.9 Hz),3.63 (2H, t, J=4.9 Hz), 3.99 (2H, t, J=4.9 Hz), 7.36-7.53 (4H, m), 7.78(1H, s), 7.84 (1H, d, J=8.3 Hz), 7.88 (1H, br s), 8.36-8.39 (1H, m),9.29 (2H, s).

[5091] MS (FAB) m/z: 516 [(M+H)⁺, Cl³⁵], 518 [(M+H)⁺, Cl³⁷].

Example A-1861-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5092] In the same manner as in Example A-182, the title compound wasobtained.

[5093]¹H-NMR (DMSO-d₆) δ: 2.71 (3H, s), 2.96 (2H, br s), 3.16 (2H, brs), 3.30 (2H, br s), 3.81 (2H, br s), 7.05 (1H, s), 7.35 (1H, d, J=8.8Hz), 7.51 (1H, d, J=8.8 Hz), 7.81 (1H, s), 8.13 (1H, br s), 8.23 (1H, brs), 8.84 (1H, br s), 9.40 (2H, s), 12.50 (1H, s).

[5094] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Example A-1874-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-Oxide

[5095] In the same manner as in Example A-6, the title compound wasobtained.

[5096]¹H-NMR (DMSO-d₆) δ: 2.77 (3H, s), 3.16-3.20 (2H, m), 3.28-3.31(2H, m), 3.57-3.60 (2H, m), 3.95-3.98 (2H, m), 6.97 (1H, d, J=1.5 Hz),7.32-7.42 (3H, m), 7.50 (1H, d, J=2.9 Hz), 7.69 (1H, s), 8.39 (1H, d,J=6.8 Hz), 8.92-9.05 (3H, m).

[5097] MS (FAB) m/z: 513 [(M+H)⁺, Cl³⁵], 515 [(M+H)⁺, Cl³⁷].

Example A-1881-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5098] In the same manner as in Example A-182, the title compound wasobtained.

[5099]¹H-NMR (DMSO-d₆) δ: 2.74 (3H, s), 3.01-3.09 (2H, m), 3.17-3.25(2H, m), 3.38-3.45 (2H, m), 3.80-3.90 (2H, m), 7.61 (1H, dd, J=8.8, 2.0Hz), 8.10 (1H, d, J=8.8 Hz), 8.13 (1H, s), 8.20 (1H, d, J=5.9 Hz), 8.31(1H, br s), 8.36 (1H, d, J=2.0 Hz), 8.87 (1H, d, J=5.9 Hz), 9.43 (2H,s).

[5100] MS (FAB) m/z: 514 [(M+H)⁺, Cl³⁵], 516 [(M+H)⁺, Cl³⁷].

Example A-1894-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-Oxide

[5101] In the same manner as in Example A-6, the title, compound wasobtained.

[5102]¹H-NMR (CDCl₃) δ: 2.60 (3H, s), 3.24 (2H, br), 3.34 (2H, br), 3.60(2H, br), 3.99 (2H, br), 7.39 (1H, dd, J=2.4 and 6.8 Hz), 7.47 (1H, dd,J=1.5 and 8.8 Hz), 7.50 (1H, d, J=2.4 Hz), 7.78 (1H, s), 7.83 (1H, d,J=8.8 Hz), 7.88 (1H, d, J=1.5 Hz), 8.38 (1H, d, J=6.8 Hz), 8.99 (2H, s).

[5103] MS (FAB) m/z: 530 [(M+H)⁺, Cl³⁵], 532 [(M+H)⁺, Cl³⁷].

Example A-1901-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(3-fluoropyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5104] In the same manner as in Example A-182, the title compound wasobtained.

[5105]¹H-NMR (DMSO-d₆) δ: 3.06 (2H, br s), 3.21 (2H, br s), 3.44 (2H, brs), 3.84 (2H, br s), 7.60 (1H, dd, J=8.8, 2.0 Hz), 7.84 (1H, dd, J=6.4,4.9 Hz), 8.09 (1H, d, J=8.8 Hz), 8.12 (1H, s), 8.35 (1H, d, J=2.0 Hz),8.62 (1H, d, J=4.9 Hz), 8.79 (1H, d, J=2.0 Hz), 9.20 (2H, s).

[5106] MS (FAB) m/z: 518 [(M+H)⁺, Cl³⁵], 520 [(M+H)⁺, Cl³⁷].

Example A-1914-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-3-fluoropyridineN-Oxide

[5107] In the same manner as in Example A-6, the title compound wasobtained.

[5108]¹H-NMR (CDCl₃) δ: 3.23-3.27 (2H, m), 3.32-3.36 (2H, m), 3.59-3.63(2H, m), 3.98-4.01 (2H, m), 7.36-7.43 (1H, m), 7.47 (1H, d, J=8.3 Hz),7.78 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.88 (1H, s), 8.18 (1H, d, J=6.8Hz), 8.30 (1H, d, J=5.9 Hz), 9.00 (2H, s).

[5109] HRMS (FAB) m/z: 534.0468 [(M+H)⁺ calcd for C₂₂H₁₈ClFN₅O₄S₂,534.0473].

Example A-1921-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5110] In the same manner as in Example A-182, the title compound wasobtained.

[5111]¹H-NMR (DMSO-d₆) δ: 2.71 (6H, s), 2.95 (2H, br s), 3.16 (2H, brs), 3.37 (2H, br s), 3.81 (2H, br s), 7.05 (1H, s), 7.35 (1H, dd, J=8.8,2.0 Hz), 7.51 (1H, d, J=8.8 Hz), 7.80 (1H, br s), 8.14 (2H, br s), 9.39(2H, s), 12.50 (1H, s).

[5112] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-1934-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,6-dimethylpyridineN-Oxide

[5113] In the same manner as in Example A-6, the title compound wasobtained.

[5114]¹H-NMR (CDCl₃) δ: 2.61 (6H, s), 3.18 (2H, d, J=4.9 Hz), 3.29 (2H,d, J=4.9 Hz), 3.59 (2H, d, J=4.9 Hz), 3.97 (2H, d, J=4.9 Hz), 6.97 (1H,d, J=1.5 Hz), 7.35 (1H, dd, J=8.8 and 2.0 Hz), 7.38-7.43 (3H, m), 7.69(1H, d, J=2.0 Hz), 8.89 (1H, br s), 8.98 (2H, s).

[5115] MS (FAB) m/z: 527 [(M+H)⁺, Cl³⁵], 529 [(M+H)⁺, Cl³⁷].

Example A-1941-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2,5-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5116] In the same manner as in Example A-182, the title compound wasobtained.

[5117]¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 2.68 (3H, s), 2.97 (2H, br s),3.16 (2H, br s), 3.40 (2H, br s), 3.81 (2H, br s), 7.06 (1H, s), 7.34(1H, dd, J=8.8 and 2.0 Hz), 7.52 (1H, d, J=8.8 Hz), 7.79-7.83 (2H, m),8.76 (1H, s), 9.32 (2H, s), 12.52 (1H, s).

[5118] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-1954-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,5-dimethylpyridineN-Oxide

[5119] In the same manner as in Example A-6, the title compound wasobtained.

[5120]¹H-NMR (CDCl₃) δ: 2.25 (3H, s), 2.54 (3H, s), 3.15-3.25 (2H, m),3.25-3.38 (2H, m), 3.55-3.65 (2H, m), 3.90-4.05 (2H, m), 6.97 (1H, s),7.13 (1H, s), 7.34 (1H, dd, J=8.8 and 1.5 Hz), 7.41 (1H, d, J=8.8 Hz),7.68 (1H, d, J=1.5 Hz), 8.28 (1H, s), 8.78 (2H, s), 9.20 (1H, s).

[5121] MS (FAB) m/z: 527 [(M+H)⁺, Cl³⁵], 529 [(M+H)⁺, Cl³⁷].

Example A-1961-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(2,3-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5122] In the same manner as in Example A-182, the title compound wasobtained.

[5123]¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.76 (3H, s), 2.97 (2H, br s),3.17 (2H, br s), 3.43 (2H, br s), 3.82 (2H, br s), 7.06 (1H, s), 7.34(1H, dd, J=8.8 and 2.0 Hz), 7.52 (1H, d, J=8.8 Hz), 7.78-7.85 (2H, m),8.72 (1H, d, J=5.9 Hz), 9.01 (2H, s), 12.52 (1H, s).

[5124] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-1974-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,3-dimethylpyridineN-Oxide

[5125] In the same manner as in Example A-6, the title compound wasobtained.

[5126]¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 2.61 (3H, s), 3.20 (2H, t, J=4.9Hz), 3.31 (2H, t, J=4.9 Hz), 3.62 (2H, t, J=4.9 Hz), 3.98 (2H, t, J=4.9Hz) 6.97 (1H, d, J=1.5 Hz), 7.00 (1H, d, J=6.8 Hz), 7.35 (1H, dd, J=8.8and 2.0 Hz), 7.40 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=2.0 Hz), 8.29 (1H,d, J=6.8 Hz), 8.75 (2H, s), 9.02 (1H, s).

[5127] MS (FAB) m/z: 527 [(M+H)⁺, Cl³⁵], 529 [(M+H)⁺, Cl³⁷].

Example A-1981-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl-4-[[5-(2,3-dimethylpyridin-4-yl)pyridimin-2-yl]carbonyl]piperazine

[5128] In the same manner as in Example A-182, the title compound wasobtained.

[5129]¹H-NMR (DMSO-d₆) δ: 2.31 (3H, s), 2.73 (3H, s), 3.05 (2H, br s),3.21 (2H, br s), 3.46 (2H, br s), 3.84 (2H, br s), 7.59 (1H, dd, J=8.5,2.0 Hz), 7.78 (1H, d, J=5.4 Hz), 8.08 (1H, d, J=8.5 Hz), 8.12 (1H, s),8.34 (1H, d, J=2.0 Hz), 8.70 (1H, d, J=5.4 Hz), 9.00 (2H, s).

[5130] MS (FAB) m/z: 528 [(M+H)⁺, Cl³⁵], 530 [(M+H)⁺, Cl³⁷].

Example A-1994-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,3-dimethylpyridineN-oxide

[5131] In the same manner as in Example A-182, the title compound wasobtained.

[5132]¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.60 (3H, s), 3.26 (2H, d, J=4.9Hz), 3.35 (2H, d, J=4.9 Hz), 3.64 (2H, d, J=4.9 Hz), 4.00 (2H, d, J=4.9Hz), 7.01 (1H, d, J=6.6 Hz), 7.47 (1H, dd, J=1.7 and 8.8 Hz), 7.78 (1H,s), 7.83 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=1.7 Hz), 8.28 (1H, d, J=6.6Hz), 8.76 (2H, s).

[5133] MS (FAB) m/z: 544 [(M+H)⁺, Cl³⁵], 546 [(M+H)⁺, Cl³⁷].

Example A-2001-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(3,5-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5134] In the same manner as in Example A-182, the title compound wasobtained.

[5135]¹H-NMR (DMSO-d₆) δ: 2.16 (6H, s), 2.99 (2H, br s), 3.17 (2H, brs), 3.42 (2H, br s), 3.82 (2H, br s), 7.06 (1H, s), 7.34 (1H, d, J=8.8Hz), 7.51 (1H, d, J=8.8 Hz), 7.80 (1H, s), 8.72 (2H, br s), 8.91 (2H,s), 12.50 (1H, s).

[5136] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-2011-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(6-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5137] In the same manner as in Example A-182, the title compound wasobtained.

[5138]¹H-NMR (DMSO-d₆) δ: 2.57 (3H, s), 2.96 (2H, br s), 3.15 (2H, brs), 3.36 (2H, br s), 3.80 (2H, br s), 7.05 (1H, d, J=2.0 Hz), 7.35 (1H,dd, J=8.8, 2.0 Hz), 7.38 (1H, d, J=7.3 Hz), 7.51 (1H, d, J=8.8 Hz), 7.81(1H, d, J=2.0 Hz), 7.89 (1H, t, J=7.3 Hz), 7.96 (1H, d, J=7.3 Hz), 9.44(2H, s), 12.49 (1H, s).

[5139] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Example A-2022-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-6-methylpyridineN-Oxide

[5140] In the same manner as in Example A-6, the title compound wasobtained.

[5141]¹H-NMR (CDCl₃) δ: 2.59 (3H, s), 3.15 (2H, d, J=4.9 Hz), 3.26 (2H,d, J=4.9 Hz), 3.56 (2H, d, J=4.9 Hz), 3.94 (2H, d, J=4.9 Hz), 6.97 (1H,s), 7.30-7.41 (5H, m), 7.69 (1H, s), 9.07 (1H, s), 9.25 (2H, s).

[5142] MS (FAB) m/z: 513 [(M+H)⁺, Cl³⁵], 515 [(M+H)⁺, Cl³⁷].

Example A-2031-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(3-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5143] In the same manner as in Example A-182, the title compound wasobtained.

[5144]¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 2.97 (2H, br s), 3.16 (2H, brs), 3.40 (2H, br s), 3.80 (2H, br s), 7.05 (1H, s), 7.33 (1H, dd, J=8.8,2.0 Hz), 7.50 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 7.84 (1H, d,J=5.4 Hz), 8.79 (1H, d, J=5.4 Hz), 8.85 (1H, s), 9.04 (2H, s), 12.49(1H, s).

[5145] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Example A-2041-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(5-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5146] In the same manner as in Example A-182, the title compound wasobtained.

[5147]¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.94-2.97 (2H, m), 3.13-3.16(2H, m), 3.35-3.39 (2H, m), 3.78-3.81 (2H, m), 7.05 (1H, d, J=2.0 Hz),7.34 (1H, dd, J=8.8, 2.0 Hz), 7.51 (1H, d, J=8.8 Hz), 7.78-7.83 (2H, m),8.07 (1H, d, J=8.3 Hz), 8.60 (1H, d, J=1.5 Hz), 9.44 (2H, s), 12.47 (1H,s).

[5148] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Example A-2052-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-5-methylpyridineN-Oxide

[5149] In the same manner as in Example A-6, the title compound wasobtained.

[5150]¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 3.16-3.19 (2H, m), 3.26-3.29 (2H,m), 3.58-3.61 (2H, m), 3.95-3.98 (2H, m), 6.98 (1H, s), 7.20-7.41 (4H,m), 7.70 (1H, s), 8.24 (1H, s), 9.04 (1H, s), 9.27 (2H, s).

[5151] MS (FAB) m/z: 513 [(M+H)⁺, Cl³⁵], 515 [(M+H)⁺, Cl³⁷].

[5152] HRMS (FAB) m/z: 513.1144 (M+H)⁺ (calcd for C₂₃H₂₂ClN₆O₄S,513.1112).

Example A-2061-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(3-methylpyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5153] In the same manner as in Example A-182, the title compound wasobtained.

[5154]¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 2.98 (2H, br s), 3.15 (2H, brs), 3.40 (2H, br s), 3.81 (2H, br s), 7.05 (1H, s), 7.34 (1H, dd, J=8.8,2.0 Hz), 7.45 (1H, dd, J=7.8, 4.9 Hz), 7.51 (1H, d, J=8.8 Hz), 7.80 (1H,s), 7.85 (1H, d, J=7.8 Hz), 8.59 (1H, d, J=4.9 Hz), 9.09 (2H, s), 12.49(1H, s).

[5155] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Example A-2071-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]thiocarbonyl]piperazine

[5156] In a mixed solvent of dimethoxyethane (10 ml) and toluene (10 ml)was suspended1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine(100 mg) at room temperature, followed by the addition of Lawesson'sreagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 42mg). The resulting mixture was heated under reflux for 2 days. Aftercooling to room temperature, the reaction mixture was concentrated andthe residue was purified by chromatography on a silica gel column (3→5%methanol methylene—chloride). 1N hydrochloric acid (in ethanol) wasadded to make acidic the purified product. After concentration, ethylacetate was added. Yellow powder so precipitated was collected byfiltration and dried, whereby the title compound (34 mg) was obtained.

[5157]¹H-NMR (DMSO-d₆) δ: 3.00 (3H, br s), 3.28 (2H, br s), 3.59 (2H, brs), 4.44 (2H, br s), 7.06 (1H, s), 7.34 (1H, dd, J=9.0, 2.0 Hz), 7.51(1H, d, J=9.0 Hz), 7.80 (1H, d, J=2.0 Hz), 8.21 (2H, d, J=6.1 Hz), 8.90(2H, d, J=6.1 Hz), 9.33 (2H, s), 12.51 (1H, s).

[5158] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

Example A-2081-[(5-Chloroindol-2-yl)sulfonyl]-4-[(hydroxyimino)[5-(pyridin-4-yl)pyrimidin-2-yl]methyl]piperazine

[5159] In ethanol (50 ml) was suspended1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]thiocarbonyl]piperazine(243 mg) at room temperature, followed by the successive addition ofhydroxylamine hydrochloride (338 mg), sodium acetate (399 mg) andmercury (II) chloride (132 mg). The resulting mixture was stirred atroom temperature for 6 hours. The insoluble matter was filtered offthrough Celite filtration. The residue was purified by chromatography ona silica gel column (7% methanol—methylene chloride), whereby twofractions were obtained. They were concentrated, respectively, whereby alow-polarity compound (20 mg, colorless powder) and a high-polaritycompound (20 mg, colorless powder) were obtained. Low-polarity compound:

[5160]¹H-NMR (DMSO-d₆) δ: 3.01 (4H, br s), 3.09 (4H, br s), 7.00 (1H,s), 7.25-7.35 (1H, m), 7.49 (1H, d, J=9.0 Hz), 7.78 (1H, br s), 7.89(2H, d, J=6.1 Hz), 8.73 (2H, d, J=6.1 Hz), 9.30 (2H, s).

[5161] HRMS (FAB) m/z: 498.1115 (M+H)⁺ (calcd for C₂₂H₂₁ClN₇O₃S,498.1115).

[5162] High-polarity compound:

[5163]¹H-NMR (DMSO-d₆) δ: 3.06 (4H, br s), 3.30-3.32 (4H, unclearbecause of the overlapping with that of water), 7.03 (1H, s), 7.33 (1H,d, J=8.8 Hz), 7.51 (1H, d, J=8.8 Hz), 7.80 (1H, br s), 7.87 (2H, d,J=6.1 Hz), 8.73 (2H, d, J=6.1 Hz), 9.24 (2H, s).

[5164] HRMS (FAB) m/z: 498.1110 (M+H)⁺ (calcd for C₂₂H₂₁ClN₇O₃S,498.1115).

Example A-209 1-[(5-Chloroindol-2-yl)sulfonyl]-4-[(hydrazono)[5-(pyridin-4-yl)pyrimidin-2-yl]methyl]piperazine

[5165] In a mixed solvent of ethanol (100 ml) and methylene chloride(100 ml) was suspended1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]thiocarbonyl]piperazine(499 mg) at room temperature, followed by the successive addition ofhydrazine monohydrate (146 μg) and mercury (II) chloride (272 mg). Theresulting mixture was stirred at room temperature for 4 hours. After thesolvent was distilled off, the residue was purified by chromatography ona silica gel column (8% methanol—methylene chloride). Methylene chloridewas added and the resulting mixture was concentrated. Yellow crystalsthus precipitated were collected by filtration and dried, whereby thetitle compound (100 mg) was obtained.

[5166]¹H-NMR (DMSO-d₆) δ: 3.03 (8H, br s), 6.77 (2H, br s), 7.04 (1H,s), 7.34 (1H, dd, J=8.8 and 2.0 Hz), 7.52 (1H, d, J=8.8 Hz), 7.81 (1H,d, J=2.0 Hz), 7.88 (2H, d, J=6.3 Hz), 8.73 (2H, d, J=6.3 Hz), 9.35 (2H,s), 12.45 (1H, s).

[5167] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

Example A-2101-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzylidene]piperazine

[5168] In the same manner as in Referential Example 7, the titlecompound was obtained.

[5169]¹H-NMR (DMSO-d₆) δ: 2.45-2.52 (2H, m), 2.57-2.61 (2H, m),3.12-3.16 (2H, m), 3.20-3.24 (2H, m), 6.44 (1H, s), 7.37 (2H, d, J=8.3Hz), 7.56 (1H, dd, J=8.5, 2.0 Hz), 7.91 (2H, d, J=8.3 Hz), 8.05 (1H, d,J=8.5 Hz), 8.07 (1H, s), 8.16 (2H, d, J=6.6 Hz), 8.31 (1H, s), 8.82 (2H,d, J=6.6 Hz).

[5170] HRMS (FAB) m/z: 481.0783 (M+H)⁺ (calcd for C₂₅H₂₂ClN₂O₂S₂,481.0811).

Example A-2111-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2-methylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5171] In the same manner as in Example A-182, the title compound wasobtained.

[5172]¹H-NMR (DMSO-d₆) δ: 2.69 (3H, s), 2.93 (2H, br s), 3.13 (2H, brs), 3.37 (2H, br s), 3.80 (2H, br s), 7.75 (1H, dd, J=8.8 and 2.0 Hz),7.84 (1H, d, J=7.8 Hz), 8.10 (1H, br s), 8.18-8.23 (2H, m), 8.26-8.32(2H, m), 8.53 (1H, br s), 8.82 (1H, d, J=5.9 Hz), 9.38 (2H, s).

[5173] MS (FAB) m/z: 508 [(M+H)⁺, Cl³⁵], 510 [(M+H)⁺, Cl³⁷].

Example A-2124-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2-methylpyridineN-Oxide

[5174] In the same manner as in Example A-6, the title compound wasobtained.

[5175]¹H-NMR (CDCl₃) δ: 2.60 (3H, s), 3.13-3.17 (2H, m), 3.25-3.28 (2H,m), 3.55-3.59 (2H, m), 3.94-3.98 (2H, m), 7.37 (1H, dd, J=6.8 and 2.9Hz), 7.49 (1H, d, J=2.9 Hz), 7.60 (1H, dd, J=8.8 and 2.0 Hz), 7.76 (1H,dd, J=8.8 and 2.0 Hz), 7.90-7.97 (3H, m), 8.31 (1H, d, J=2.0 Hz), 8.37(1H, d, J=6.8 Hz), 8.97 (2H, s).

[5176] MS (FAB) m/z: 524 [(M+H)⁺, Cl³⁵], 526 [(M+H)⁺, Cl³⁷].

Example A-2131-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5177] In the same manner as in Example A-182, the title compound wasobtained.

[5178]¹H-NMR (DMSO-d₆) δ: 2.93 (2H, br s), 3.12 (2H, br s), 3.36 (2H, brs), 3.81 (2H, br s), 7.50 (1H, dd, J=7.3 and 4.9 Hz), 7.74 (1H, dd,J=8.8 and 2.0 Hz), 7.83 (1H, dd, J=8.8 and 1.5 Hz), 7.96-8.03 (1H, m),8.16 (1H, d, J=8.3 Hz), 8.19 (1H, d, J=8.8 Hz), 8.25-8.31 (2H, m), 8.52(1H, br s), 8.75 (1H, d, J=4.9 Hz), 9.46 (2H, s).

[5179] MS (FAB) m/z: 494 [(M+H)⁺, Cl³⁵], 496 [(M+H)⁺, Cl³⁷].

Example A-2142-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5180] In the same manner as in Example A-6, the title compound wasobtained.

[5181]¹H-NMR (CDCl₃) δ: 3.13-3.16 (2H, m), 3.24-3.27 (2H, m), 3.57-3.60(2H, m), 3.93-3.97 (2H, m), 7.38-7.44 (2H, m), 7.46-7.50 (1H, m), 7.59(1H, dd, J=8.8 and 2.0 Hz), 7.77 (1H, dd, J=8.8 and 2.0 Hz), 7.91-7.96(3H, m), 8.31 (1H, br s), 8.35-8.38 (1H, m), 9.26 (2H, s).

[5182] MS (FAB) m/z: 510 [(M+H)⁺, Cl³⁵], 512 [(M+H)⁺, Cl³⁷].

Example A-2151-[[5-(Pyridin-4-yl)pyrimidin-2-yl]carbonyl]-4-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine

[5183] In a 1N aqueous hydrochloric acid in ethanol was dissolved1-(tert-butoxycarbonyl)-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine(739 mg), followed by stirring at room temperature for 30 minutes. Thesolvent was distilled off under reduced pressure. To the residue wereadded N,N-dimethylformamide (15 ml), triethylamine (2 ml) and6-trimethylsilylethynylbenzo[b]thiophen-2-sulfonyl chloride (740 mg) andthe resulting mixture was stirred at room temperature for 3 hours. Thereaction mixture was diluted with methylene chloride, washed with water(thrice), dried over anhydrous sodium sulfate and purified bychromatography on a silica gel column (hexane:ethylacetate=1:0→1:1→ethyl acetate:methylene chloride=3:1→0:1→methylenechloride:methanol=100:2→100:7), whereby the title compound (167 mg) wasobtained as a white solid.

[5184]¹H-NMR (CDCl₃) δ: 0.28 (9H, s), 3.25 (2H, t, J=4.9 Hz), 3.35 (2H,t, J=4.9 Hz), 3.61 (2H, t, J=4.9 Hz), 4.00 (2H, t, J=4.9 Hz), 7.51 (2H,dd, J=4.4, 1.5 Hz), 7.55 (1H, dd, J=8.3, 1.5 Hz), 7.78 (1H, s), 7.83(1H, d, J=8.3 Hz), 8.00 (1H, s), 8.80 (2H, dd, J=4.4, 1.5 Hz), 9.03 (2H,s).

[5185] MS (FAB) m/z: 567 (M+H)⁺.

Example A-2164-[[5-(Pyridin-4-yl)pyrimidin-2-yl]carbonyl]-1-[(6-ethynylbenzo[b]thien-2-[b]thien-2-yl)sulfonyl]piperazine

[5186] In a mixed solvent of tetrahydrofuran (5 ml) and methanol (7 ml)was dissolved1-[[5-(4-pyridyl)pyrimidin-2-yl]carbonyl]-4-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine(167 mg), followed by the addition of potassium hydroxide (34 mg). Theresulting mixture was stirred at room temperature for 30 minutes. Thereaction mixture was made weakly acidic with a saturated aqueoussolution of ammonium chloride, and then made weakly alkaline with asaturated aqueous solution of sodium bicarbonate. After concentrationunder reduced pressure, the concentrate was extracted (4 times) withmethylene chloride. The organic layers were combined, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (methylene chloride:methanol=1:0→24:1). The resulting amorphouswas dissolved in methylene chloride, followed by the dropwise additionto hexane to precipitate the resulting mixture as powder. The titlecompound (112 mg) was obtained as a white solid.

[5187]¹H-NMR (CDCl₃) δ: 3.23 (1H, s), 3.25 (2H, t, J=5.1 Hz), 3.35 (2H,t, J=5.1 Hz), 3.61 (2H, t, J=5.1 Hz), 4.00 (2H, t, J=5.1 Hz), 7.51 (2H,dd, J=4.4, 1.5 Hz), 7.58 (1H, dd, J=8.3, 0.98 Hz), 7.79 (1H, s), 7.86(1H, d, J=8.3 Hz) 8.02 (1H, s), 8.80 (2H, dd, J=4.4, 1.5 Hz), 9.02 (2H,s).

[5188] MS (FAB) m/z: 490 (M+H)⁺.

Example A-2171-[(5-Chloroisoindolin-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine

[5189] In the same manner as in Example A-4, the title compound wasobtained.

[5190]¹H-NMR (CDCl₃) δ: 3.22-3.80 (8H, m), 4.63-4.65 (4H, m), 7.37 (1H,d, J=8.3 Hz), 7.37 (1H, m), 7.43 (1H, s), 7.64 (2H, d, J=8.3 Hz), 8.04(2H, d, J=8.3 Hz), 8.20-8.14 (2H, br), 8.9 (2H, d, J=5.4 Hz).

[5191] MS (FAB) m/z: 483 [(M+H)⁺, Cl³⁵], 485 [(M+H)⁺, Cl³⁷].

Example A-2184-[4-[[4-[(5-Chloroisoindolin-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[5192] In the same manner as in Example A-6, the title compound wasobtained.

[5193]¹H-NMR (DMSO-d₆) δ: 3.25-3.77 (8H, m), 4.62-4.65 (4H, m),7.33-7.39 (2H, m), 7.43 (1H, s), 7.54 (2H, d, J=8.3 Hz), 7.81 (1H, d,J=6.8 Hz), 7.86 (2H, d, J=8.3 Hz), 8.28 (2H, d, J=6.8 Hz).

[5194] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

Example A-2194-[(5-Chloroindol-2-yl)sulfonyl]-2-ethyl-1-[[5-pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5195] In the same manner as in Example A-182, the title compound wasobtained.

[5196]¹H-NMR (DMSO-d₆) δ: 0.75 (1.5H, t, J=7.8 Hz), 0.94 (1.5H, t, J=7.8Hz), 1.60-1.89 (2H, m), 2.23-2.57 (2H, m), 3.14 (0.5H, m), 3.25-3.43(1H, m), 3.45-3.90 (2.5H, m), 4.44-4.53 (0.5H, m), 4.65-4.72 (0.5H, m),7.04 (1H, t, J=2.4 Hz), 7.34 (1H, dt, J=8.8, 2.4 Hz), 7.50 (1H, dd,J=8.8, 2.4 Hz), 7.80 (1H, t, J=2.4 Hz), 8.18 (2H, br), 8.90 (2H, br),9.39 (2H, t, J=2.4 Hz), 12.48 (1H, br).

[5197] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-2204-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-ethylpiperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5198] In the same manner as in Example A-6, the title compound wasobtained.

[5199]¹H-NMR (DMSO-d₆) δ: 0.74 (1.5H, t, J=7.3 Hz), 0.93 (1.5H, t, J=7.3Hz), 1.03-1.09 (0.5H, m), 1.58-1.68 (0.5H, m), 1.70-1.90 (1.5H, m),2.13-2.57 (2H, m), 3.13-3.21 (0.5H, m), 3.25-3.60 (2H, m), 3.70-3.76(0.5H, m), 3.78-3.86 (0.5H, m), 4.45-4.52 (0.5H, m), 4.67 (0.5H, br),7.04 (1H, m), 7.34 (1H, dt, J=8.8, 2.4 Hz), 7.50 (1H, dd, J=8.8, 2.4Hz), 7.80 (1H, t, J=2.4 Hz), 7.90 (2H, dd, J=7.3, 2.4 Hz), 8.38 (2H, t,J=7.3, 3.4 Hz), 9.29 (2H, d, J=4.5 Hz), 12.46 (1H, br).

[5200] MS (FAB) m/z: 517 [(M+H)⁺, Cl³⁵], 519 [(M+H)⁺, Cl³⁷].

Example A-2214-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-ethyl-1-[(5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine

[5201] In the same manner as in Example A-182, the title compound wasobtained.

[5202]¹H-NMR (DMSO-d₆) δ: 0.77 (1.5H, t, J=7.8 Hz), 0.95 (1.5H, t, J=7.8Hz), 1.62-1.70 (0.5H, m), 1.73-1.82 (0.5H, m), 1.83-1.93 (1H, m),2.44-2.71 (2H, m), 3.14-3.24 (0.5H, m), 3.35-3.62 (2H, m), 3.67-3.76(1H, m), 3.79-3.85 (0.5H, m), 4.47-4.53 (0.5H, m), 4.67-4.74 (0.5H, m),7.57-7.62 (1H, m), 8.03-8.14 (4H, m), 8.33-8.37 (1H, m), 8.83 (1H, d,J=4.6 Hz), 9.36 (2H, d, J=3.7 Hz).

[5203] MS (FAB) m/z: 528 [(M+H)⁺, Cl³⁵], 530 [(M+H)⁺, Cl³⁷].

Example A-2224-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-ethylpiperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5204] In the same manner as in Example A-6, the title compound wasobtained.

[5205]¹H-NMR (DMSO-d₆) δ: 0.76 (1.5H, t, J=7.3 Hz), 0.94 (1.5H, t, J=7.3Hz), 1.15-1.28 (0.5H, m), 1.60-1.69 (0.5H, m), 1.70-1.92 (1.5H, m),2.50-2.60 (1H, m), 2.62-2.71 (1H, m), 3.12-3.24 (0.5H, m), 3.35-3.45(1H, m), 3.50-3.61 (1H, m), 3.64-3.87 (1H, m), 4.47-4.54 (0.5H, m),4.67-4.74 (0.5H, m), 7.58-7.63 (1H, m), 7.94-8.00 (2H, m), 8.06-8.13(2H, m), 8.34-8.40 (3H, m), 9.30 (2H, d, J=2.0 Hz).

[5206] MS (FAB) m/z: 544 [(M+H)⁺, Cl³⁵], 546 [(M+H)⁺, Cl³⁷].

Example A-2234-[(5-Chloroindol-2-yl)sulfonyl]-2-ethyl-1-[(5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine

[5207] In the same manner as in Example A-182, the title compound wasobtained.

[5208]¹H-NMR (DMSO-d₆) δ: 0.74 (1.5H, t, J=7.3 Hz), 0.94 (1.5H, t, J=7.3Hz), 1.02-1.13 (0.5H, m), 1.57-1.68 (0.5H, m), 1.70-1.89 (2H, m),2.25-2.49 (1H, m), 3.10-3.23 (0.5H, m), 3.27-3.59 (2.5H, m), 3.68-3.87(1H, m), 4.45-4.52 (0.5H, m), 4.63-4.71 (0.5H, m), 7.03-7.05 (1H, m),7.32-7.36 (1H, m), 7.50 (2H, d, J=8.3, 2.4 Hz), 7.79 (1H, br), 7.98-8.02(1H, m), 8.16 (1H, d, J=7.8 Hz), 8.75-8.77 (1H, m), 9.48 (2H, br), 12.46(1H, br).

[5209] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-2242-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-ethylpiperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5210] To a methylene chloride solution (50 ml) of4-[(5-chloroindol-2-yl)sulfonyl]-2-(ethyl)-1-[(5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine(234 mg) was added metachloroperbenzoic acid (1.58 g) at roomtemperature. The resulting mixture was stirred for 5 hours. An aqueoussolution (20 ml) of sodium sulfite was added, followed by stirring for 1hour. To the reaction mixture were added a saturated aqueous solution ofsodium bicarbonate and methylene chloride. The water layer was extractedthrice with methylene chloride. The organic layers were combined, driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was subjected to chromatography on asilica gel column (methanol:methylene chloride=1:50). The oil thusobtained was solidified from ethanol—diethyl ether, whereby the titlecompound (44.1 mg) was obtained as a pale yellow solid.

[5211] MS (FAB) m/z: 527 [(M+H)⁺, Cl³⁵], 529 [(M+H)⁺, Cl³⁷]

[5212]¹H-NMR (DMSO-d₆) δ: 0.75 (1.5H, t, J=7.3 Hz), 0.93 (1.5H, t, J=7.3Hz), 1.05-1.13 (0.5H, m), 1.58-1.92 (2.5H, m), 2.29-2.78 (1H, m),3.13-3.89 (4H, m), 4.40-4.52 (0.5H, m), 4.62-4.71 (0.5H, m), 7.04 (1H,d, J=3.4 Hz), 7.32-7.37 (1H, m), 7.47-7.55 (3H, m), 7.78-7.82 (1H, m),7.86-7.90 (1H, m), 8.42 (1H, d, J=5.9 Hz), 9.33 (2H, br), 12.44 (1H,br).

Example A-2251-[(5-Chloroindol-2-yl)sulfonyl]-4-[5-(pyridin-3-yl)thiazol-2-yl]piperazine

[5213] To a solution of 3-(5-thiazolyl)pyridine (400 mg) in diethylether (15 mg), n-butyl lithium (a 1.52 N hexane solution, 1.45 ml) wasadded dropwise at −78° C. After stirring for 30 minutes, a carbondioxide gas was blown into the reaction mixture. After 10 minutes, acooling bath was removed and the temperature of the reaction mixture wasallowed to rise back slowly to room temperature. The reaction mixturewas concentrated, whereby the residue of lithium5-(3-pyridyl)thiazole-2-carboxylate was obtained as a white solid. To asolution of the resulting residue in N,N-dimethylformamide (10 ml) wereadded 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride (600 mg),1-hydroxybenzotriazole monohydrate (255 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360 mg) atroom temperature. After stirring for 3 days, ethyl acetate (50 ml) andwater (100 ml) were added to the reaction mixture. The white precipitatethus obtained was collected by filtration and washed with water andethyl acetate, whereby the title compound (727 mg) was obtained as apale brown solid. A portion of the compound was added with an aqueoussolution of hydrochloric acid, followed by concentration and drying. Theproduct thus obtained showed the following data.

[5214]¹H-NMR (DMSO-d₆) δ: 3.32 (4H, br s), 3.94 (2H, br s), 4.59 (2H, brs), 7.20 (1H, s), 7.47 (1H, d, J=8.8 Hz), 7.65 (1H, d, J=8.8 Hz),7.66-7.76 (1H, m), 7.93 (1H, s), 8.36 (1H, d, J=8.3 Hz), 8.63 (1H, brs), 8.78 (1H, s), 9.16 (1H, s), 12.61 (1H, s).

[5215] MS (FAB) m/z: 488 (M+H)⁺.

Example A-2263-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5216] In the same manner as in Example A-6, the title compound wasobtained.

[5217]¹H-NMR (DMSO-d₆) δ: 3.31 (4H, br s), 3.93 (2H, br s), 4.57 (2H, brs), 7.19 (1H, s), 7.46 (1H, d, J=8.8 Hz), 7.50-7.70 (2H, m), 7.80 (1H,d, J=8.3 Hz), 7.92 (1H, s), 8.05 (1H, s), 8.39 (1H, d, J=6.4 Hz), 8.67(1H, br s), 8.93 (1H, s), 12.61 (1H, br s).

[5218] MS (FAB) m/z: 504 (M+H)⁺, 488 (M+H−O)⁺.

Example A-2271-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine

[5219] A saturated solution of hydrochloride in methanol (12 ml) wasadded to1-(t-butoxycarbonyl)-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine(400 mg) at room temperature. After stirring for 10 minutes, thereaction mixture was concentrated under reduced pressure, whereby1-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine hydrochloride wasobtained as a white solid. In a solution of the resulting hydrochloridein methylene chloride (12 ml) was dissolved5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (522 mg), followed bythe addition of diisopropylethylamine (538 μl) at room temperature.After stirring for 3 hours, a saturated aqueous solution (50 ml) ofsodium bicarbonate was added to the reaction mixture to separate it intolayers. The water layer was extracted with methylene chloride (2×15 ml).The organic layers were combined, dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. The residuewas purified by chromatography on a silica gel column (methylenechloride:acetone=7:1), whereby the title compound (240 mg) was obtainedas a foam.

[5220]¹H-NMR (CDCl₃) δ: 2.63 (3H, s), 3.55 (2H, s), 3.60 (2H, s), 3.92(2H, s), 4.60 (2H, s), 7.31 (1H, d, J=5.4 Hz), 7.35 (1H, s), 7.40-7.52(4H, m), 7.52-7.65 (2H, m), 8.03 (2H, d, J=7.3 Hz), 8.14 (1H, s), 8.23(1H, d, J=9.3 Hz), 8.56 (1H, d, J=5.4 Hz).

Example A-2281-[(5-Chloroindol-2-yl)sulfonyl]-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine

[5221] In the same manner as in Example A-99, the title compound wasobtained.

[5222]¹H-NMR (DMSO-d₆) δ: 2.88 (3H, s), 3.33 (4H, br s), 3.95 (2H, brs), 4.57 (2H, br s), 7.20 (1H, d, J=2.0 Hz), 7.47 (1H, dd, J=8.8, 2.0Hz), 7.66 (1H, d, J=8.8 Hz), 7.93 (1H, d, J=2.0 Hz), 8.32 (1H, d, J=6.4Hz), 8.40 (1H, br s), 8.94 (1H, d, J=6.4 Hz), 9.02 (1H, d, J=2.0 Hz),12.66 (1H, s).

[5223] MS (FAB) m/z: 502 [(M+H)⁺, Cl³⁵], 504 [(M+H)⁺, Cl³⁷].

Example A-2294-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]-2-methylpyridineN-Oxide

[5224] In the same manner as in Example A-6, the title compound wasobtained.

[5225]¹H-NMR (DMSO-d₆) δ: 3.28 (4H, br s), 3.47 (3H, s), 3.91 (2H, br),4.56 (2H, br s), 7.17 (1H, s), 7.44 (1H, dd, J=8.8, 2.0 Hz), 7.62 (1H,d, J=8.8 Hz), 7.81 (1H, dd, J=6.8, 2.7 Hz), 7.90 (1H, d, J=2.0 Hz), 8.04(1H, d, J=2.7 Hz), 8.43 (1H, d, J=6.8 Hz), 8.59 (1H, s), 12.57 (1H, brs).

[5226] MS (FAB) m/z: 518 (M+H)⁺, 502 (M+H−O)⁺.

Example A-2301-[(5-Ethynylindol-2-yl)sulfonyl]-4-[5-(pyridin-4-yl)thiazol-2-yl]piperazine

[5227] A saturated solution of hydrochloride in methanol (12 ml) wasadded to1-(tert-butoxycarbonyl)-4-[5-(pyridin-4-yl)thiazol-2-yl]piperazine (400mg) at room temperature. After stirring for 1 hour, the reaction mixturewas concentrated under reduced pressure, whereby the residue, that is,1-[5-(pyridin-4-yl)thiazol-2-yl]piperazine hydrochloride was obtained asa white solid. In a solution of the resulting residue in methylenechloride (15 ml) was dissolved[1-phenylsulfonyl-5-(trimethylsilylethynyl)indol-2-yl]sulfonyl chloride(630 mg), followed by the addition of diisopropylethylamine (746 μl) at0° C. After stirring for 4 hours, methylene chloride (10 ml) and asaturated aqueous solution (30 ml) of sodium bicarbonate were added tothe reaction mixture to separate it into layers. The water layer wasextracted with methylene chloride (2×10 ml). The organic layers werecombined, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column (methylene chloride acetone=6:1),whereby1-[5-(2-methylpyridin-4-yl)thiazol-2-yl)-4-[[1-phenylsulfonyl-5-(trimethylsilylethynyl)indol-2-yl]sulfonyl]piperazine(214 mg) was obtained as a foam. To a solution of the resulting residuein tetrahydrofuran (10 ml) were added methanol (10 ml), morpholine (54.0μl) and potassium hydroxide (52.0 mg), followed by stirring at roomtemperature for 3 hours. A saturated aqueous solution (30 ml) of sodiumbicarbonate, methylene chloride (30 ml) and water (10 ml) were added tothe reaction mixture to separate it into layers. The water layer wasextracted with methylene chloride (10 ml). The organic layers werecombined, dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bypreparative thin-layer chromatography (methylene chloride:acetone=6:1)using silica gel, whereby the title compound (84.8 mg) was obtained as awhite solid. The solid was dissolved in tetrahydrofuran, followed by theaddition of water. The resulting mixture was concentrated, whereby awhite solid was obtained. The solid showed the following data:

[5228]¹H-NMR (DMSO-d₆) δ: 3.15 (4H, br s), 3.77 (2H, br s), 4.01 (1H,s), 4.41 (2H, br s), 7.05 (1H, s), 7.34 (1H, d, J=8.5 Hz), 7.44 (1H, d,J=8.5 Hz), 7.72 (2H, d, J=4.9 Hz), 7.85 (1H, s), 8.58 (1H, s), 8.63 (2H,d, J=4.9 Hz), 12.42 (1H, br s).

[5229] MS (FAB) m/z: 478 (M+H)⁺.

Example A-2314-[2-[[4-[(5-Ethynylindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5230] In the same manner as in Example A-6, the title compound wasobtained.

[5231]¹H-NMR (DMSO-d₆) δ: 3.16 (4H, br s), 3.77 (2H, br s), 4.02 (1H,s), 4.41 (2H, br s), 7.06 (1H, s), 7.36 (1H, d, J=8.5 Hz), 7.46 (1H, d,J=8.5 Hz), 7.78 (2H, d, J=6.9 Hz), 7.86 (1H, s), 8.26 (2H, d, J=6.9 Hz),8.48 (1H, s), 12.43 (1H, br s).

[5232] MS (FAB) m/z: 494 (M+H)⁺, 478 (M+H−O)⁺.

Example A-2321-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazineHydrochloride

[5233] In the same manner as in Example A-7, the title compound wasobtained.

[5234]¹H-NMR (DMSO-d₆) δ: 3.14 (4H, br s), 3.79 (2H, br s), 4.41 (2H, brs), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.11(2H, d, J=5.9 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=2.0 Hz), 8.25(1H, d, J=8.8 Hz), 8.51 (1H, s), 8.77 (1H, s), 8.79-8.85 (2H, m).

[5235] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

Example A-2334-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5236] In the same manner as in Example A-6, the title compound wasobtained.

[5237]¹H-NMR (DMSO-d₆) δ: 3.13 (4H, br s), 3.77 (2H, br s), 4.43 (2H, brs), 7.69 (1H, d, J=8.8 Hz), 7.76 (2H, d, J=6.4 Hz), 7.82 (1H, d, J=8.8Hz), 8.15 (1H, d, J=8.8 Hz), 8.20-8.28 (5H, m), 8.46 (1H, s), 8.50 (1H,s).

[5238] MS (FAB) m/z: 515 [(M+H)⁺, Cl³⁵], 517 [(M+H)⁺, Cl³⁷].

Example A-2341-[(6-Chloronaphthalen-2-yl)sulfon-yl]-4-[[5-(pyridin-2-yl)thiazol-2-yl]carbonyl]piperazineHydrochloride

[5239] In the same manner as in Example A-4, the title compound wasobtained.

[5240]¹H-NMR (DMSO-d₆) δ: 3.13 (4H, br s), 3.77 (2H, br s), 4.42 (2H, brs), 7.37 (1H, m), 7.69 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, d, J=8.8 Hz),7.89 (1H, m), 8.03 (1H, d, J=7.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.21 (1H,d, J=2.0 Hz), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, s), 8.56 (1H, s), 8.57(1H, d, J=4.4 Hz).

[5241] MS (FAB) m/z: 499 [(M+H)⁺, Cl³⁵], 501 [(M+H)⁺, Cl³⁷].

Example A-2352-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5242] In the same manner as in Example A-6, the title compound wasobtained.

[5243]¹H-NMR (DMSO-d₆) δ: 3.14 (4H, br s), 3.78 (2H, br s), 4.41 (2H, brs), 7.47 (1H, t, J=7.8 Hz), 7.54 (1H, t, J=7.8 Hz), 7.68 (1H, dd, J=8.8,2.0 Hz), 7.84 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.20 (1H, s),8.25 (1H, d, J=8.8 Hz), 8.42-8.51 (3H, m), 8.95 (1H, s).

[5244] MS (FAB) m/z: 515 [(M+H)⁺, Cl³⁵], 517 [(M+H)⁺, Cl³⁷].

Example A-2361-[(5-Chloroindol-2-yl)sulfonyl]-4-[[5(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazineHydrochloride

[5245] In the same manner as in Example A-4, the title compound wasobtained.

[5246]¹H-NMR (DMSO-d₆) δ: 3.18 (4H, br s), 3.80 (2H, br s), 4.41 (2H, brs), 7.04 (1H, s), 7.30 (1H, dd, J=8.8, 1.5 Hz), 7.49 (1H, d, J=8.8 Hz),7.76 (1H, s), 8.15 (2H, d, J=5.9 Hz), 8.79 (1H, s), 8.84 (2H, d, J=5.9Hz), 12.44 (1H, s).

[5247] MS (FAB) m/z: 488 [(M+H)⁺, Cl³⁵], 490 [(M+H)⁺, Cl³⁷].

Example A-2374-[2-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5248] In the same manner as in Example A-6, the title compound wasobtained.

[5249]¹H-NMR (DMSO-d₆) δ: 3.16 (4H, br s), 3.78 (2H, br s), 4.43 (2H, brs), 7.03 (1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.47 (1H, d, J=8.8 Hz),7.75 (1H, d, J=2.0 Hz), 7.77 (2H, d, J=7.3 Hz), 8.25 (2H, d, J=7.3 Hz),8.30 (1H, s), 8.47 (1H, s), 12.41 (1H, s).

[5250] MS (FAB) m/z: 504 [(M+H)⁺, Cl³⁵], 506 [(M+H)⁺, Cl³⁷].

Example A-2381-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazineHydrochloride

[5251] In the same manner as in Example A-4, the title compound wasobtained.

[5252]¹H-NMR (DMSO-d₆) δ: 3.24 (4H, br s), 3.84 (2H, br s), 4.46 (2H, brs), 7.50-7.65 (3H, m), 8.03-8.10 (2H, m), 8.30 (1H, s), 8.76 (1H, s),8.80 (2H, m).

[5253] MS (FAB) m/z: 505 [(M+H)⁺, Cl³⁵], 507 [(M+H)⁺, Cl³⁷].

Example A-2394-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5254] In the same manner as in Example A-6, the title compound wasobtained.

[5255]¹H-NMR (DMSO-d₆) δ: 3.22 (4H, br s), 3.82 (2H, br s), 4.47 (2H, brs), 7.54 (1H, dd, J=8.8, 2.0 Hz), 7.78 (2H, d, J=7.3 Hz), 8.05 (1H, d,J=8.8 Hz), 8.09 (1H, s), 8.25 (2H, d, J=7.3 Hz), 8.29 (1H, s), 8.48 (1H,s).

[5256] MS (FAB) m/z: 521 [(M+H)⁺, Cl³⁵], 523 [(M+H)⁺, Cl³⁷].

Example A-2401-[(5-Chloroindol-2-yl)sulfonyl]-4-[[3-(pyridin-4-yl)-1,2,4-triazin-6-yl]carbonyl]piperazineHydrochloride

[5257] Ethyl 3-(pyridin-4-yl)-1,2,4-triazin-6-carboxylate (200 mg) wasdissolved in a mixed solvent of tetrahydrofuran (5 ml) and methanol (5ml) at room temperature. A 1N aqueous solution (1.00 ml) of sodiumhydroxide was added to the reaction mixture in one portion. Afterstirring for 5 minutes, the reaction mixture was distilled under reducedpressure to remove tetrahydrofuran and methanol, followed byneutralization with 1N hydrochloric acid. The reaction mixture wasconcentrated to dryness, whereby3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid was obtained as acrudely purified product.

[5258] In N,N-dimethylformamide (10 ml) were suspended3-(pyridin-4-yl)-1,2,4-triazine-6-carboxylic acid and1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride (292 mg) atroom temperature. To the reaction mixture were successively added1-hydroxybenzotriazole (117 mg), N-methylmorpholine (191 μl) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg),followed by stirring overnight. After completion of the reaction, thesolvent was distilled off under reduced pressure. Water and ethylacetate were added to the residue to separate into layers. The organiclayer was dried over magnesium sulfate and the filtrate wasconcentrated. Ethanol was added to the residue. Yellow crystals thusprecipitated were collected by filtration and dried, whereby the freeform (282 mg) of the title compound was obtained. The free form wassuspended in ethanol and the resulting suspension was made acidic by theaddition of 1N hydrochloric acid (in ethanol) and a small amount ofwater. After concentration of the resulting solution, ethanol and ethylacetate were added and the resulting mixture was concentrated again.Crystals thus precipitated were collected by filtration and dried,whereby the title compound was obtained.

[5259]¹H-NMR (DMSO-d₆) δ: 3.05-3.09 (2H, m), 3.18-3.21 (2H, m),3.69-3.72 (2H, m), 3.84-3.88 (2H, m), 7.05 (1H, d, J=1.5 Hz), 7.33 (1H,dd, J=8.8, 2.0 Hz), 7.50 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz),8.45-8.52 (2H, m), 8.92-8.98 (2H, m), 9.17 (1H, d, J=1.0 Hz), 12.47 (1H,s).

[5260] MS (FAB) m/z: 484 [(M+H)⁺, Cl³⁵], 486 [(M+H)⁺, Cl³⁷].

Example A-2414-[6-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,2,4-triazin-3-yl]pyridineN-Oxide

[5261] In the same manner as in Example A-6, the title compound wasobtained.

[5262]¹H-NMR (DMSO-d₆) δ: 3.06 (2H, br), 3.18 (2H, br), 3.70 (2H, br),3.85 (2H, br), 7.05 (1H, s), 7.32 (1H, dd, J=8.8, 2.0 Hz), 7.49 (1H, d,J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 8.34 (2H, d, J=7.3 Hz), 8.40 (2H, d,J=7.3 Hz), 9.06 (1H, s), 12.45 (1H, s).

[5263] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵], 502 [(M+H)⁺, Cl³⁷].

Example A-2421-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[2,5-dihydro-5-oxo-6-(pyridin-4-yl)-1,2,4-triazin-3-yl]carbonyl]piperazineHydrochloride

[5264] In the same manner as in Example A-4, the title compound wasobtained.

[5265]¹H-NMR (DMSO-d₆) δ: 3.00-3.09 (2H, m), 3.10-3.17 (2H, m),3.75-3.81 (4H, m), 7.74 (1H, dd, J=8.8 and 2.0 Hz), 7.86 (1H, d, J=8.8Hz), 8.20 (1H, d, J=8.8 Hz), 8.25-8.35 (4H, m), 8.55 (1H, br s), 8.86(2H, d, J=5.4 Hz).

[5266] MS (FAB) m/z: 511 [(M+H)⁺, Cl³⁵], 513 [(M+H)⁺, Cl³⁷].

Example A-2431-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[5267] In the same manner as in Example A-182, the title compound wasobtained.

[5268]¹H-NMR (DMSO-d₆) δ: 2.71 (6H, s), 2.94 (2H, br s), 3.13 (2H, brs), 3.37 (2H, br s), 3.80 (2H, br s), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.83(1H, d, J=8.8 Hz), 8.13 (2H, br s), 8.13 (1H, d, J=8.8 Hz), 8.27-8.30(2H, m), 8.52 (1H, s), 9.38 (2H, s).

[5269] MS (FAB) m/z: 522 [(M+H)⁺, Cl³⁵], 524 [(M+H)⁺, Cl³⁷].

Example A-2444-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]-2,6-dimethylpyridineN-Oxide

[5270] In the same manner as in Example A-6, the title compound wasobtained.

[5271]¹H-NMR (CDCl₃) δ: 2.61 (6H, s), 3.15 (2H, d, J=4.8 Hz), 3.26 (2H,d, J=4.8 Hz), 3.57 (2H, d, J=4.8 Hz), 3.96 (2H, d, J=4.9 Hz), 7.37 (2H,s), 7.60 (1H, dd, J=8.8, 2.0 Hz), 7.76 (1H, dd, J=8.8, 1.5 Hz),7.91-7.97 (3H, m), 8.31 (1H, s), 8.96 (2H, s).

[5272] MS (FAB) m/z: 538 [(M+H)⁺, Cl³⁵], 540 [(M+H)⁺, Cl³⁷].

Example A-2451-[(5-Chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)phenylsulfonyl]piperazine

[5273] A saturated solution of hydrochloride in methanol (10 ml) wasadded to1-(tert-butoxycarbonyl)-4-[4-(pyridin-4-yl)phenylsulfonyl]piperazine(180 mg). After stirring for 30 minutes, the solvent was distilled offunder reduced pressure. To the residue were added methylene chloride (10ml), 5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (260 mg) anddiisopropylethylamine (235 μg) at room temperature. After stirring for 4hours, methylene chloride (10 ml) and a saturated aqueous solution (30ml) of sodium bicarbonate were added the reaction mixture to separate itinto layers. The water layer was extracted with methylene chloride. Theorganic layers were combined, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (methylenechloride:acetone=5:1→3:1), whereby the title compound (131 mg) wasobtained as a pale yellow foam.

[5274]¹H-NMR (CDCl₃) δ: 3.18 (4H, s), 3.57 (4H, s), 7.37-7.46 (4H, m),7.50-7.59 (4H, m), 7.80 (2H, d, J=8.3 Hz), 7.85 (2H, d, J=8.3 Hz), 7.86(2H, d, J=8.3 Hz), 8.12 (1H, d, J=8.8 Hz), 8.76 (2H, br d, J=4.4 Hz).

Example A-2461-[(5-Chloroindol-2-yl)sulfonyl]-4-[4(pyridin-4-yl)phenylsulfonyl]piperazineHydrochloride

[5275] In the same manner as in Example A-103, the title compound wasobtained.

[5276]¹H-NMR (DMSO-d₆) δ: 3.05 (4H, br t, J=4.0 Hz), 3.18 (4H, br t,J=4.0 Hz), 6.97 (1H, d, J=1.5 Hz), 7.16 (1H, dd, J=8.8, 1.9 Hz), 7.40(1H, d, J=8.8 Hz), 7.68 (1H, d, J=1.9 Hz), 7.83 (2H, d, J=8.5 Hz), 8.09(2H, d, J=8.5 Hz), 8.19 (2H, d, J=6.6 Hz), 8.97 (2H, d, J=6.6 Hz), 12.40(1H, br s).

[5277] MS (FAB) m/z: 517 (M+H)⁺.

Example A-2474-[4-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]sulfonyl]phenyl]pyridineN-Oxide

[5278] In the same manner as in Example A-6, the title compound wasobtained.

[5279]¹H-NMR (DMSO-d₆) δ: 3.00 (4H, br t, J=4.6 Hz), 3.17 (4H, br t,J=4.0 Hz), 6.96 (1H, s), 7.18 (1H, dd, J=9.1, 1.7 Hz), 7.39 (1H, d,J=9.1 Hz), 7.69 (1H, d, J=1.7 Hz), 7.73 (2H, d, J=8.3 Hz), 7.82 (2H, d,J=6.8 Hz), 7.93 (2H, d, J=8.3 Hz), 8.34 (2H, d, J=6.8 Hz), 12.35 (1H, brs).

[5280] MS (FAB) m/z: 533 (M+H)⁺.

Example A-2481-[(5-Chloroindol-2-yl)carbonyl]-4-[4-(pyridin-4-yl)phenylsulfonyl]piperazineHydrochloride

[5281] A saturated solution of hydrochloride in methanol (10 ml) wasadded to1-(tert-butoxycarbonyl)-4-[4-(pyridin-4-yl)phenylsulfonyl]piperazine(180 mg). After stirring for 30 minutes, the solvent was distilled offunder reduced pressure. To a solution of the residue inN,N-dimethylformamide (10 ml) were added (5-chloroindol-2-yl)carboxylicacid (90.0 mg), 1-hydroxybenzotriazole (75.5 mg) and1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg) anddiisopropylethylamine (233 μg) at room temperature. After stirring for 3days, methylene chloride (100 ml) and water (500 ml) were added to thereaction mixture to separate it into layers. The water layer wasextracted with methylene chloride (50 ml). The organic layers werecombined, washed with water (500 ml) and a saturated aqueous solution(100 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (silica gel: 20 g,methylene chloride:acetone=3:1→1:1), whereby the title compound (97.5mg) was obtained as a white solid. The resulting compound was dissolvedin hydrochloric acid—methanol—methylene chloride—tetrahydrofuran,followed by concentration, whereby the title compound was obtained.

[5282] Hydrochloride:

[5283]¹H-NMR (DMSO-d₆) δ: 3.10 (4H, br s), 3.84 (4H, br s), 6.76 (1H, d,J=1.5 Hz), 7.17 (1H, dd, J=8.8, 2.0 Hz), 7.39 (1H, d, J=8.8 Hz), 7.62(1H, d, J=2.0 Hz), 7.96 (2H, d, J=8.3 Hz), 8.22 (2H, d, J=8.3 Hz), 8.30(2H, d, J=6.4 Hz), 8.97 (2H, d, J=6.4 Hz), 11.76 (1H, br s).

[5284] MS (FAB) m/z: 481 (M+H)⁺.

Example A-2494-[4-[[4-[(5-Chloroindol-2-yl)carbonyl]piperazin-1-yl]sulfonyl]phenyl]pyridineN-Oxide

[5285] In the same manner as in Example A-6, the title compound wasobtained.

[5286]¹H-NMR (DMSO-d₆) δ: 3.07 (4H, br s), 3.83 (4H, br s), 6.75 (1H,s), 7.18 (1H, br d, J=8.8 Hz), 7.39 (1H, d, J=8.8 Hz), 7.62 (1H, br s),7.85 (2H, d, J=8.3 Hz), 7.88 (2H, d, J=6.6 Hz), 8.07 (2H, d, J=8.3 Hz),8.33 (2H, d, J=6.6 Hz), 11.74 (1H, br s).

[5287] MS (FAB) m/z: 497 (M+H)⁺.

Example A-2504-[(5-Chloroindol-2-yl)sulfonyl]-1-[(5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]-2-(2-methlpropyl)piperazine

[5288] In the same manner as in Example A-182, the title compound wasobtained.

[5289]¹H-NMR (DMSO-d₆) δ: 0.84-1.62 (2H, m), 1.75 (3H, s), 1.77 (3H, s),2.26-2.41 (1H, m), 2.55-2.70 (1H, m), 3.18-3.50 (2H, m), 3.55-3.68 (1H,m), 3.70-4.45 (2H, m), 5.36-5.58 (1H, m), 7.04 (1H, s), 7.34 (1H, d,J=8.8 Hz), 7.51 (1H, d, J=8.8 Hz), 7.80 (1H, s), 8.16 (2H, br), 8.90(2H, br), 9.37 (2H, s), 12.48 (1H, br).

[5290] MS (FAB) m/z: 539 [(M+H)⁺, Cl³⁵], 541 [(M+H)⁺, Cl³⁷].

Example A-2514-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-1-[(5-(pyridin-4-yl)pyrimidin-2-yl)carbonyl]-2-(2-methylpropyl)piperazine

[5291] In the same manner as in Example A-182, the title compound wasobtained.

[5292]¹H-NMR (DMSO-d₆) δ: 0.64-1.68 (3H, m), 1.75 (3H, s), 1.77 (3H, s),2.25-2.58 (1H, m), 2.60-2.83 (1H, m), 2.87-4.23 (4H, m), 4.40-4.53 (1H,m), 7.06 (1H, s), 7.34 (1H, d, J=8.8 Hz), 7.49 (1H, d, J=8.8 Hz), 7.81(1H, s), 8.15 (2H, br), 8.88 (2H, br), 9.37 (2H, br), 12.48 (1H, s).

[5293] MS (FAB) m/z: 556 [(M+H)⁺, Cl³⁵], 558 [(M+H)⁺, Cl³⁷].

Example A-2521-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,2-dimethyl-4-[4-(pyridin-4-yl)benzoyl]piperazine

[5294] In the same manner as in Example A-4, the title compound wasobtained.

[5295]¹H-NMR (DMSO-d₆) δ: 1.14 (3H, br s), 1.28 (3H, br s), 3.20-3.90(6H, br), 7.53-7.70 (2H, br), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.90 (1H,br), 7.96-8.08 (2H, m), 8.14 (1H, d, J=8.8 Hz), 8.20-8.33 (4H, m), 8.57(1H, s), 8.92 (2H, br).

[5296] MS (FAB) m/z: 520 [(M+H)⁺, Cl³⁵], 522 [(M+H)⁺, Cl³⁷].

Example A-2534-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-3,3-dimethylpiperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[5297] In the same manner as in Example A-6, the title compound wasobtained.

[5298]¹H-NMR (CDCl₃) δ: 1.26 (3H, br), 1.39 (3H, br), 3.26 (1H, br),3.50-3.95 (5H, br), 7.45-7.55 (4H, br), 7.58 (1H, dd, J=8.8, 2.0 Hz),7.62 (2H, d, J=7.8 Hz), 7.79 (1H, d, J=7.8 Hz), 7.89 (2H, d, J=7.8 Hz),7.92 (1H, s), 8.27 (2H, br), 8.37 (1H, s).

[5299] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

Example A-2544-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,2-dimethyl-1-[4-(pyridin-4-yl)benzoyl]piperazine

[5300] In the same manner as in Example A-26, the title compound wasobtained.

[5301]¹H-NMR (DMSO-d₆) δ: 1.50 (6H, s), 3.10 (2H, s), 3.20-3.30 (2H, brt), 3.50 (2H, br), 7.58 (2H, d, J=7.8 Hz), 7.73 (1H, dd, J=8.8, 2.0 Hz),7.87 (1H, dd, J=8.8, 2.0 Hz), 7.98 (2H, d, J=7.8 Hz), 8.19 (1H, d, J=8.8Hz), 8.20-8.30 (3H, m)-, 8.30 (1H, d, J=7.8 Hz), 8.53 (1H, s), 8.90 (2H,d, J=5.9 Hz).

[5302] MS (FAB) m/z: 520 [(M+H)⁺, Cl³⁵], 522 [(M+H)⁺, Cl³⁷].

Example A-2554-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazin-1-yl]carbonyl]phenyl]pyridineN-Oxide

[5303] In the same manner as in Example A-6, the title compound wasobtained.

[5304]¹H-NMR (CDCl₃) δ: 1.60 (5H, br), 3.04 (2H, s), 3.20 (2H, t, J=4.9Hz), 3.48 (2H, t, J=4.9 Hz), 7.40-7.50 (4H, m), 7.56 (2H, d, J=8.8 Hz),7.61 (1H, dd, J=8.8, 2.0 Hz), 7.79 (1H, dd, J=8.8, 2.0 Hz), 7.88-7.96(1H, m), 7.95 (2H, d, J=7.8 Hz), 8.25 (2H, d, J=7.8 Hz), 8.34 (1H, s).

[5305] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

Example A-2564-[(5-Chloroindol-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)-1-[[4-(pyridin-4-yl)-3-cyclohexen-1-yl]carbonyl]piperazine

[5306] In a mixture of methylene chloride (30 mL) andN,N-dimethylformamide (30 mL) was dissolved 4-(pyridin-4-yl)-3-hexenicacid hydrochloride (480 mg). Under ice cooling,1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)piperazine(1.024 g), 1-hydroxybenzotriazole (405 mg), N-methylmorpholine (0.607mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (575mg) were added to the resulting solution. After 10 minutes, the mixturewas allowed to rise back to room temperature, followed by stirring.After 48 hours, the reaction was terminated and the solvent wasdistilled off under reduced pressure. Ethyl acetate was added to theresidue. The resulting mixture was washed with a saturated aqueoussolution of sodium bicarbonate and saturated saline, dried overanhydrous magnesium sulfate and distilled under reduced pressure toremove the solvent. The residue was subjected to chromatography on asilica gel column (methylene chloride:methanol=20:1), whereby the titlecompound (680 mg, colorless oil) was obtained.

[5307]¹H-NMR (CDCl₃) δ: 1.14 (1H, t, J=7.1 Hz), 1.22 (1H, t, J=7.1 Hz),1.64-3.87 (14H, m), 3.69 (3H, s), 6.33-6.42 (1H, m), 6.97 (1H, m),7.21-7.40 (4H, m), 7.67 (1H, d, J=2 Hz), 8.54 (2H, m).

[5308] MS (FAB) m/z: 557 (M+H)⁺.

Example A-257 Sodium[4-[(5-chloroindol-2-yl)sulfonyl]-1-[[4-(pyridin-4-yl)-3-cyclohexen-1-yl]carbonyl]piperazin-2-yl]acetate

[5309] In a 100-mL egg-plant type flask was charged4-[(5-chloroindo-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)-1-[[4-(pyridin-4-yl)-3-hexen-1-yl]carbonyl]piperazine(680 mg), followed by dissolution in methanol (20 mL). A 1N sodiumhydroxide solution (5 mL) was added to the resulting solution and theresulting mixture was stirred at 70° C. After 23 hours, the reaction wasterminated. After concentration, the crystals were collected byfiltration, whereby the title compound (320 mg, colorless solid) wasobtained as a sodium salt.

[5310]¹H-NMR (CDCl₃) δ: 1.10-3.90 (16H, m), 6.40-6.48 (1H, m), 6.95 (1H,d, J=2.9 Hz), 7.19 (1H, dd, J=8.8, 2.0 Hz), 7.41 (3H, m), 7.64 (1H, d,J=2.5 Hz), 8.40 (2H, m).

Example A-2584-[(5-Chloroindol-2-yl)sulfonyl]-2-[(piperidin-1-yl)carbonylmethyl]-1-[[4-(pyridin-4-yl)-3-cyclohexen-1-yl]carbonyl]piperazine

[5311] In the same manner as in Example A-4, the title compound wasobtained.

[5312]¹H-NMR (CDCl₃) δ: 1.61-3.82 (24H, m), 4.65-4.93 (2H, m), 6.96-7.68(5H, m), 8.02 (1H, s), 8.51 (2H, m).

Example A-2594-[4-[[4-[(5-Chloroindol-2-yl)sulfonyl]-2-[(piperidin-1-yl)carbonylmethyl]piperazin-1-yl]carbonyl]-1-cyclohexen-1-yl]pyridineN-Oxide

[5313] In the same manner as in Example A-6, the title compound wasobtained.

[5314]¹H-NMR (DMSO-d₆) δ: 1.63-4.94 (26H, m), 6.28 (1H, m), 6.99 (1H,m), 7.18-7.40 (4H, m), 7.65 (1H, d, J=15.4 Hz), 8.13 (1H, d, J=4.9 Hz).

[5315] MS (FAB) m/z: 626 [(M+H)⁺, Cl³⁵].

Example A-2601-[((E)-4-Chloro-2-methoxystyryl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[5316] In the same manner as in Example A-105, the title compound wasobtained.

[5317]¹H-NMR (DMSO-d₆) δ: 3.07 (2H, br), 3.24 (2H, br), 3.39 (2H, br),3.82 (2H, br), 3.92 (2H, s), 7.10 (1H, dd, J=8.3, 1.5 Hz), 7.23 (1H, d,J=1.5 Hz), 7.29 (1H, d, J=15.6 Hz), 7.56 (1H, d, J=15.6 Hz), 7.84 (1H,d, J=8.3 Hz), 8.34 (2H, d, J=6.1 Hz), 8.98 (2H, d, J=6.1 Hz), 9.46 (2H,s).

[5318] MS (FAB) m/z: 500 [(M+H)⁺, Cl³⁵]₆ 502 [(M+H)⁺, Cl³⁷].

Example A-2611-[((E)-4-Chloro-2-hydroxystyryl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[5319] In methylene chloride (18 ml) was dissolved1-[((E)-4-chloro-2-methoxystyryl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine(366 mg), followed by the addition of boron tribromide (a 1.0 molesolution, methylene chloride) at −78° C. in an argon atmosphere. Theresulting mixture was stirred at −78° C. for 0.5 hour and 0° C. for 2hours. The reaction mixture was distilled under reduced pressure. Aftera saturated aqueous solution of sodium bicarbonate and water were addedto the residue and the insoluble matter was filtered off, methylenechloride was added for extraction. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was subjectedto column chromatography (10% methanol—methylene chloride) using as acarrier silica gel and then chromatography on a silica gel column(methylene chloride˜5% methanol—methylene chloride), whereby a crudelypurified product (146 mg) was obtained. A portion (81.0 mg) of theproduct was dissolved in tetrahydrofuran. To the resulting solution wasadded 1N aqueous hydrochloric acid in ethanol. The resulting mixture wassolidified, followed by collection by filtration. The resulting solidwas then dissolved in methanol. After filtration of the resultingsolution, water was added. The solvent was distilled off under reducedpressure, whereby the title compound (68.5 g) was obtained as colorlesspowder.

[5320]¹H-NMR (DMSO-d₆) δ: 3.00-3.10 (2H, m), 3.20-3.25 (2H, m),3.35-3.45 (2H, m), 3.80-3.85 (2H, m), 6.94 (1H, d, J=8.3 Hz), 7.05 (1H,s), 7.24 (1H, d, J=15.6 Hz), 7.55 (1H, d, J=15.6 Hz), 7.74 (1H, d, J=8.3Hz), 8.36 (2H, br s), 8.95-9.05 (2H, m), 9.47 (2H, s), 11.10 (1H, br s).

[5321] MS (FAB) m/z: 486 [(M+H)⁺, Cl³⁵], 488 [(M+H)⁺, Cl³⁷].

Example A-2624-[2-[[4-[((E)-4-Chloro-2-hydroxystyryl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5322] In the same manner as in Example A-105, the title compound wasobtained.

[5323]¹H-NMR (DMSO-d₆) δ: 3.00-3.10 (2H, m), 3.15-3.25 (2H, m),3.35-3.40 (2H, m), 3.75-3.85 (2H, m), 6.90-7.00 (2H, m), 7.23 (1H, d,J=15.6 Hz), 7.54 (1H, d, J=15.6 Hz), 7.74 (1H, d, J=8.3 Hz), 7.97 (2H,d, J=7.8 Hz), 8.45-50 (2H, m), 9.32 (2H, s), 10.95 (1H, br s).

[5324] MS (FAB) m/z: 502 [(M+H)⁺, Cl³⁵], 504 [(M+H)⁺, Cl³⁷].

Example A-2632,cis-6-Bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[5325] In the same manner as in Example A-105, the title compound wasobtained.

[5326]¹H-NMR (CDCl₃) δ: 2.50-2.80 (3H, m), 2.95-3.05 (2H, m), 3.10-3.20(1H, m), 3.65-3.75 (1H, m), 3.68 (3H, s), 3.75 (3H, s), 4.00-4.10 (1H,m), 4.15-4.25 (1H, m), 5.15-5.25 (1H, m), 7.40-7.50 (2H, m), 7.55-7.60(1H, m), 7.70-7.75 (1H, m), 7.90-7.95 (3H, m), 8.30 (1H, s), 8.75-8.85(2H, m), 8.96 (2H, s).

Example A-2642,cis-6-Bis(carbamoylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[5327] In tetrahydrofuran (10 ml) and methanol (5 ml) were dissolved2,cis-6-bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine(372 mg), followed by the dropwise addition of a mixture of sodiumhydroxide (310 ml) and water (1.6 ml) under ice cooling. The resultingmixture was stirred at room temperature for 23.5 hours. Afterconcentrated hydrochloric acid was added to the reaction mixture to makeit acidic, the solvent was distilled off under reduced pressure. Theresidue was suspended in N,N-dimethylformamide (15 ml), followed by theaddition of di-tert-butyl dicarbonate (665 mg), pyridine (290 μl) andammonium bicarbonate (304 mg) under ice cooling. The resulting mixturewas stirred at room temperature for 19 hours. After completion of thethe stirring, the solvent was distilled off under reduced pressure. Theresidue was subjected to chromatography on a silica gel column(methylene chloride˜20% methanol methylene—chloride), whereby a crudelypurified product (182 mg) was obtained. A 62.3 mg portion of theresulting product was subjected to chromatography on a silica gel column(methylene chloride˜15% methanol—methylene chloride). The solvent wasthen distilled off under reduced pressure. Ethyl acetate was added tothe residue to solidify the same, whereby the title compound (23 mg) wasobtained as pale yellow powder.

[5328]¹H-NMR (DMSO-d₆) δ: 2.25-2.35 (1H, m), 2.40-2.60 (3H, m),2.80-3.00 (2H, m), 3.50-3.60 (1H, m), 3.8-3.95 (2H, m), 4.90-5.00 (1H,m), 6.90 (1H, br s), 7.06 (1H, br s), 7.45 (1H, br s), 7.53 (1H, br s),7.70-7.75 (1H, m), 7.75-7.85 (1H, m), 7.85-7.95 (2H, m), 8.17 (1H, d,J=8.8 Hz), 8.25-8.35 (2H, m), 8.51 (1H, s), 8.70-8.75 (1H, m), 9.31 (2H,s).

[5329] MS (FAB) m/z: 608 [(M+H)⁺, Cl³⁵], 610 [(M+H)⁺, Cl³⁷].

Example A-2654-[2-[[2,cis-6-Bis(carbamoylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5330] In the same manner as in Example A-6, the title compound wasobtained.

[5331]¹H-NMR (DMSO-d₆) δ: 2.25-2.35 (1H, m), 2.40-2.60 (3H, m),2.80-3.00 (2H, m), 3.55-3.60 (1H, m), 3.85-3.95 (2H, m), 4.90-5.00 (1H,m), 6.89 (1H, br s), 7.06 (1H, br s), 7.43 (1H, br s), 7.51 (1H, br s),7.70-7.75 (1H, m), 7.75-7.85 (1H, m), 7.97 (2H, d, J=7.3 Hz), 8.16 (1H,d, J=8.8 Hz), 8.20-8.40 (4H, m), 8.51 (1H, s), 9.29 (2H, s).

[5332] MS (FAB) m/z: 624 [(M+H)⁺, Cl³⁵], 626 [(M+H)⁺, Cl³⁷].

Example A-2664-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[5333] In the same manner as in Example A-105, the title compound wasobtained.

[5334]¹H-NMR (CDCl₃) δ: 2.45-3.30 (6H, m), 3.50-5.40 (6H, m), 3.67, 3.74(3H, each s), 7.45-7.50 (2H, m), 7.55-7.65 (1H, m), 7.70-7.80 (1H, m),7.90-7.95 (3H, m), 8.29 (1H, br s), 8.78 (2H, d, J=5.4 Hz), 8.99, 9.00(2H, each s).

Example A-2674-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5335] In tetrahydrofuran (10 ml) and methanol (5.0 ml) was dissolved4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(methoxycarbonylmethyl)-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine(583 mg). Under ice cooling, a mixture of sodium hydroxide (200 mg) andwater (1.0 ml) was added dropwise to the resulting solution under icecooling, followed by stirring at room temperature for 5 hours. Under icecooling, concentrated hydrochloric acid (420 μl) was added to thereaction mixture to make it weakly acidic. The reaction mixture was thendistilled under reduced pressure. To the residue were added morpholine(102 μl), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(239 mg) and 1-hydroxybenzotriazole hydrate (159 mg). The resultingmixture was dissolved in N,N-dimethylformamide (60 ml) and methylenechloride (30 ml). Diisopropylethylamine (760 μl) was added dropwise tothe resulting solution under ice cooling, followed by stirring at roomtemperature for 12.5 hours. The reaction mixture was distilled underreduced pressure. A 100% aqueous solution of citric acid was added tothe residue and it was extracted with methylene chloride. The organiclayer was washed with a saturated aqueous solution of sodium bicarbonateand saturated aqueous NaCl solution, dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. The residuewas subjected to column chromatography (10% methanol—methylene chloride)using as a carrier silica gel, followed by crystallization frommethylene chloride—tetrahydrofuran, whereby a crudely purified product(349 mg) was obtained. A portion (161 mg) of the product was dissolvedin methylene chloride—methanol. To the resulting solution was added 1Naqueous hydrochloride in ethanol (260 μl) and the mixture wasconcentrated to dryness. Ethyl acetate was added to the concentrate andthe solid thus obtained was collected by filtration, washed with ethylacetate and dried, whereby the title compound (117 mg) was obtained ascolorless powder.

[5336]¹H-NMR (CDCl₃) δ: 2.25-5.15 (17H, m), 7.70-7.75 (1H, m), 7.82 (1H,d, J=8.8 Hz), 8.15-8.30 (5H, m), 8.51 (1H, br s), 8.90-9.00 (2H, m),9.35-9.45 (2H, m).

[5337] MS (FAB) m/z: 621 [(M+H)⁺, Cl³⁵], 623 [(M+H)⁺, Cl³⁷].

Example A-2682,cis-6-Bis[(N-methylcarbamoyl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5338] In the same manner as in Example A-264, the title compound wasobtained.

[5339]¹H-NMR (DMSO-d₆) δ: 2.20-2.70 (10H, m), 2.70-2.90 (2H, m),3.40-4.10 (3H, m), 4.90-5.00 (1H, m), 7.73 (1H, d, J=7.8 Hz), 7.81 (1H,d, J=7.8 Hz), 7.94 (1H, d, J=4.4 Hz), 8.01 (1H, d, J=4.4 Hz), 8.17 (1H,d, J=8.3 Hz), 8.20-8.40 (4H, m), 8.52 (1H, s), 8.98 (2H, d, J=5.9 Hz),9.43 (2H, s).

[5340] MS (FAB) m/z: 636 [(M+H)⁺, Cl³⁵], 638 [(M+H)⁺, Cl³⁷].

Example A-2692,cis-6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5341] In the same manner as in Example A-264, the title compound wasobtained.

[5342]¹H-NMR (DMSO-d₆) δ: 2.50-3.10 (6H, m), 2.73 (3H, s), 2.86 (3H, s),2.97 (3H, s), 3.04 (3H, s), 3.53 (1H, d, J=11.7 Hz), 3.84 (1H, d, J=12.2Hz), 3.99 (1H, d, J=9.8 Hz), 5.02 (1H, d, J=10.8 Hz), 7.71 (1H, dd,J=9.0, 2.2 Hz), 7.79 (1H, dd, J=8.5, 1.7 Hz), 8.17 (1H, d, J=8.8 Hz),8.20-8.35 (4H, m), 8.51 (1H, s), 8.90-8.95 (2H, m), 9.35-9.45 (2H, m).

[5343] MS (FAB) m/z: 664 [(M+H)⁺, Cl³⁵], 666 [(M+H)⁺, Cl³⁷].

Example A-2704-[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5344] In the same manner as in Example A-6, the title compound wasobtained.

[5345]¹H-NMR (CDCl₃) δ: 2.25-5.15 (17H, m), 7.70-7.75 (1H, m), 7.80-7.85(1H, m), 7.90-8.00 (2H, m), 8.18 (1H, d, J=8.8 Hz), 8.20-8.30 (2H, m),8.30-8.40 (2H, m), 8.49 (1H, br s), 9.26 (2H, d, J=7.8 Hz).

[5346] MS (FAB) m/z: 637 [(M+H)⁺, Cl³⁵], 639 [(M+H)⁺, Cl³⁷].

Example A-2714-[2-[[2,cis-6-Bis(N,N-dimethycarbamoylmethyl)-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5347] In the same manner as in Example A-6, the title compound wasobtained.

[5348]¹H-NMR (CDCl₃) δ: 2.50-3.30 (6H, m), 2.91 (3H, m), 3.00 (3H, m),3.08 (3H, m), 3.12 (3H, m), 3.70 (1H, d, J=12.2 Hz), 4.16 (1H, d, J=12.7Hz), 4.37 (1H, d, J=10.7 Hz), 5.20-5.30 (1H, m), 7.50 (2H, d, J=7.3 Hz),7.57 (1H, dd, J=8.8, 2.0 Hz), 7.72 (1H, dd, J=8.6, 1.7 Hz), 7.85-7.95(3H, m), 8.25-8.35 (3H, m), 8.91 (2H, s).

[5349] MS (FAB) m/z: 680 [(M+H)⁺, Cl³⁵], 682 [(M+H)⁺, Cl³⁷].

Example A-2724-[2-[[2,cis-6-Bis(N-methylcarbamoylmethyl)-4-(6-chloronaphthalen-2-ylsulfonyl)piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5350] In the same manner as in Example A-6, the title compound wasobtained.

[5351]¹H-NMR (CD₃OD) δ: 2.50-2.80 (4H, m), 2.66 (3H, s), 2.78 (3H, s),2.90-3.00 (2H, m), 3.64 (1H, d, J=12.7 Hz), 4.01 (1H, d, J=12.2 Hz),4.20 (1H, d, J=9.8 Hz), 5.10-5.15 (1H, m), 7.62 (1H, dd, J=8.8, 2.0 Hz),7.78 (1H, dd, J=8.8, 1.5 Hz), 7.97 (2H, d, J=7.3 Hz), 8.00-8.10 (3H, m),8.35-8.45 (3H, m), 9.20 (2H, s).

[5352] MS (FAB) m/z: 652 [(M+H)⁺, Cl³⁵], 654 [(M+H)⁺, Cl³⁷].

Example A-2732-[2-(tert-Butyldiphenylsilyloxy)ethyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[5353] In the same manner as in Example A-105, the title compound wasobtained.

[5354]¹H-NMR (CDCl₃) δ: 0.84, 1.09 (9H, each s), 2.10-2.20 (2H, m),2.35-2.65 (2H, m), 3.15-5.25 (7H, m), 7.10-7.80 (14H, m), 7.85-8.00 (3H,m), 8.20-8.30 (1H, m), 8.65-9.00 (4H, m).

[5355] MS (FAB) m/z: 776 [(M+H)⁺, Cl³⁵], 778 [(M+H)⁺, Cl³⁷].

Example A-2744-(6-Chloronaphthalen-2-ylsulfonyl)-2-(2-hydroxyethyl)-1-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[5356] In pyridine (6.0 ml) was dissolved2-[(tert-butyldiphenylsilyloxy)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine(150 mg). A hydrogen fluoride—pyridine complex (2.0 ml) was addeddropwise to the resulting solution under ice cooling, followed bystirring at 0° C. for 1.5 hours. Ethyl acetate (40 ml) was added to thereaction mixture to dilute it. Then, the diluted mixture was poured intoice. The resulting mixture was extracted. The organic layer was washedwith saturated saline, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was subjectedto column chromatography (5% methanol—methylene chloride˜10%methanol—methylene chloride) using as a carrier silica gel, whereby acrudely purified product (97.9 mg) was obtained. The resulting productwas dissolved in methylene chloride, followed by the addition of 1Nhydrochloric acid in ethanol (182 μl) for solidification.Tetrahydrofuran was added to the residue to solidify the same, wherebythe title compound (62.7 mg) was obtained as colorless crystallinepowder.

[5357]¹H-NMR (DMSO-d₆) δ: 2.20-5.20 (9H, m), 6.90-7.05 (1H, m),7.50-7.60 (2H, m), 7.70-7.90 (2H, m), 8.00-8.10 (1H, m), 8.19 (1H, d,J=8.3 Hz), 8.25-8.35 (2H, m), 8.40-8.50 (3H, m), 9.00 (2H, d, J=5.9 Hz).

[5358] MS (FAB) m/z: 538 [(M+H)⁺, Cl³⁵], 540 [(M+H)⁺, Cl³⁷].

Example A-2752-cis,6-Bis(methoxycarbonylmethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[[5-(pyridin-4-yl)pyrimidin-2-yl]piperazine

[5359] In the same manner as in Example A-105, the title compound wasobtained.

[5360]¹H-NMR (CDCl₃) δ: 2.70-2.85 (3H, m), 2.95-3.15 (3H, m), 3.65-3.75(1H, m), 3.67 (3H, s), 3.75 (3H, s), 4.02 (1H, d, J=12.7 Hz), 4.29 (1H,d, J=9.8 Hz), 5.25-5.35 (1H, m), 7.45-7.55 (3H, m), 7.75-7.90 (3H, m),8.75-8.85 (2H, m), 8.98 (2H, s).

[5361] MS (FAB) m/z: 644 [(M+H)⁺, Cl³⁵], 646 [(M+H)⁺, Cl³⁷].

Example A-2762-[(tert-Butyldiphenylsilyloxy)methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5362] In the same manner as in Example A-105, the title compound wasobtained.

[5363]¹H-NMR (DMSO-d₆) δ: 0.95 (9H×0.5, s), 1.04 (9H×0.5, s), 2.50-3.60(4H, m), 3.70-3.90 (2H, m), 3.95-4.10 (2H, m), 4.45-5.00 (1H, m),7.30-7.55 (7H, m), 7.55-7.65 (2H, m), 7.70-7.75 (2H, m), 8.05-8.15 (2H,m), 8.25-8.40 (3H, m), 8.95-9.05 (2H, m), 9.25-9.35 (1H, m), 9.40-9.45(1H, m).

[5364] MS (FAB) m/z: 768 [(M+H)⁺, Cl³⁵], 770 [(M+H)⁺, Cl³⁷].

Example A-2774-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(hydroxymethyl)-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5365] In the same manner as in Example A-274, the title compound wasobtained.

[5366]¹H-NMR (DMSO-d₆) δ: 2.40-2.70 (2H, m), 3.10-4.00 (6H, m),4.45-4.75 (1H, m), 7.55-7.65 (1H, m), 8.05-8.15 (2H, m), 8.35 (1H, s),8.40-8.45 (2H, m), 9.03 (2H, d, J=4.4 Hz), 9.46 (2H, s).

[5367] MS (FAB) m/z: 530 [(M+H)⁺, Cl³⁵], 532 [(M+H)⁺, Cl³⁷].

Example A-2782,cis-6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[5368] In the same manner as in Example A-264, the title compound wasobtained.

[5369]¹H-NMR (DMSO-d₆) δ: 2.40-3.80 (7H, m), 2.74 (3H, s), 2.87 (3H, s),2.98 (3H, s), 3.05 (3H, s), 3.83 (1H, d, J=12 Hz), 4.00-4.05 (1H, m),5.06 (1H, d, J=8.7 Hz), 7.58 (1H, dd, J=8.8, 2.0 Hz), 8.07 (1H, d, J=8.8Hz), 8.10-8.20 (3H, m), 8.35 (1H, s), 8.87 (2H, d, J=5.4 Hz), 9.39 (2H,s).

[5370] MS (FAB) m/z: 670 [(M+H)⁺, Cl³⁵], 672 [(M+H)⁺, Cl³⁷].

Example A-2794-[2-[[2,cis-6-Bis[(N,N-dimethylcarbamoyl)methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5371] In the same manner as in Example A-6, the title compound wasobtained.

[5372]¹H-NMR (DMSO-d₆) δ: 2.40-3.10 (4H, m), 2.74 (3H, s), 2.87 (3H, s),3.04 (3H, s), 3.33 (3H, s), 3.40-3.50 (2H, m), 3.52 (1H, d, J=11.7 Hz),3.82 (1H, d, J=12.7 Hz), 4.03 (1H, d, J=6.8 Hz), 5.05 (1H, d, J=10.3Hz), 7.59 (1H, dd, J=8.8, 2.0 Hz), 7.99 (2H, d, J=7.3 Hz), 8.07 (1H, d,J=8.3 Hz), 8.12 (1H, s), 8.30-8.40 (3H, m), 9.30 (2H, s).

[5373] MS (FAB) m/z: 686 [(M+H)⁺, Cl³⁵], 688 [(M+H)⁺, Cl³⁷].

Example A-2804-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(hydroxymethyl)piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5374] In the same manner as in Example A-6, the title compound wasobtained.

[5375]¹H-NMR (DMSO-d₆) δ: 2.40-2.70 (2H, m), 3.10-4.00 (6H, m), 4.47(1H, d, J=13.7 Hz), 4.67 (1H, br s), 4.89 (1H, t, J=5.4 Hz), 5.16 (1H,t, J=5.4 Hz), 7.55-7.65 (1H, m), 7.90-8.00 (2H, m), 8.05-8.15 (2H, m),8.30-8.40 (3H, m), 9.30 (2H, s).

[5376] MS (FAB) m/z: 546 [(M+H)⁺, Cl³⁵], 548 [(M+H)⁺, Cl³⁷].

Example A-2812-[2-(tert-Butyldiphenylsilyloxy)ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5377] In the same manner as in Example A-105, the title compound wasobtained.

[5378]¹H-NMR (DMSO-d₆) δ: 0.79, 1.02 (9H, each s), 1.70-5.10 (11H, m),7.35-7.70 (12H, m), 8.05-8.40 (4H, m), 8.90-9.05 (2H, m), 9.35, 9.45(2H, each s).

[5379] MS (FAB) m/z: 782 [(M+H)⁺, Cl³⁵], 784 [(M+H)⁺, Cl³⁷].

Example A-2824-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-hydroxyethyl)-1-[5-(pyridin-4-yl)pyrimidin-2-yl]piperazineHydrochloride

[5380] In the same manner as in Example A-274, the title compound wasobtained.

[5381]¹H-NMR (DMSO-d₆) δ: 1.80-2.00 (2H, m), 2.40-3.90 (9H, m),4.45-5.00 (1H, m), 7.55-7.65 (1H, m), 8.05-8.15 (2H, m), 8.35-8.45 (3H,m), 9.01 (2H, d, J=7.8 Hz), 9.45 (2H, d, J=2.4 Hz).

[5382] MS (FAB) m/z: 544 [(M+H)⁺, Cl³⁵], 546 [(M+H)⁺, Cl³⁷].

Example A-2832-[2-(tert-Butyldiphenylsilyloxy)ethyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-1-[5-(pyridin-2-yl)pyrimidin-2-yl]piperazine

[5383] In the same manner as in Example A-182, the title compound wasobtained.

[5384]¹H-NMR (DMSO-d₆) δ: 0.82, 1.09 (9H, each s), 2.05-2.20 (2H, m),2.55-2.80 (2H, m), 3.15-4.25 (6H, m), 4.70-5.30 (1H, m), 7.10-7.55 (11H,m), 7.70-7.90 (6H, m), 8.70-8.80 (1H, m), 9.22, 9.34 (2H, each s).

[5385] MS (FAB) m/z: 782 [(M+H)⁺, Cl³⁵], 784 [(M+H)⁺, Cl³⁷].

Example A-2844-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-hydroxyethyl)-1-[5-(pyridin-2-yl)pyrimidin-2-yl]piperazineHydrochloride

[5386] In the same manner as in Example A-274, the title compound wasobtained.

[5387]¹H-NMR (DMSO-d₆) δ: 1.80-2.00 (2H, m), 2.40-3.90 (9H, m),4.45-5.00 (1H, m), 7.50-7.65 (2H, m), 8.00-8.15 (3H, m), 8.15-8.25 (1H,m), 8.34 (1H, s), 8.77 (1H, d, J=4.4 Hz), 9.48 (2H, s).

[5388] MS (FAB) m/z: 544 [(M+H)⁺, Cl³⁵], 546 [(M+H)⁺, Cl³⁷].

Example A-2854-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(methoxycarbonyl)methyl]-1-[5-(pyridin-2-yl)pyrimidin-2-yl]piperazine

[5389] In the same manner as in Example A-182, the title compound wasobtained.

[5390]¹H-NMR (CDCl₃) δ: 2.60-3.30 (5H, m), 3.50-5.45 (7H, m), 7.20-7.55(2H, m), 7.70-7.90 (5H, m), 8.76 (1H, d, J=4.9 Hz), 8.76 (2H, d, J=2.4Hz).

[5391] MS (FAB) m/z: 572 [(M+H)⁺, Cl³⁵], 574 [(M+H)⁺, Cl³⁷].

Example A-2862-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(methoxycarbonyl)methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5392] In the same manner as in Example A-6, the title compound wasobtained.

[5393]¹H-NMR (CDCl₃) δ: 2.60-3.30 (4H, m), 3.50-5.40 (5H, m), 3.67, 3.74(3H, each s), 7.30-7.55 (4H, m), 7.70-7.90 (3H, m), 8.30-8.40 (1H, m),9.29 (2H, d, J=12.2 Hz).

[5394] MS (FAB) m/z: 572 [(M+H)⁺, Cl³⁵], 574 [(M+H)⁺, Cl³⁷].

Example A-2872-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5395] In the same manner as in Example A-267, the title compound wasobtained.

[5396]¹H-NMR (DMSO-d₆) δ: 2.30-2.80 (3H, m), 2.74 (3H, s), 2.85 (3H, s),2.92 (3H, s), 3.01 (3H, s), 3.10-4.15 (5H, m), 4.50-5.15 (1H, m),7.45-7.65 (3H, m), 7.85-7.95 (1H, m), 8.05-8.15 (2H, m), 8.34 (1H, s),8.40-8.45 (1H, m), 9.35 (2H, s).

[5397] MS (FAB) m/z: 601 [(M+H)⁺, Cl³⁵], 603 [(M+H)⁺, Cl³⁷].

Example A-2882-[2-[[2-(2-tert-Butyldiphenylsilyloxyethyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5398] In the same manner as in Example A-6, the title compound wasobtained.

[5399]¹H-NMR (CDCl₃) δ: 0.80-1.10 (9H, m), 2.00-2.20 (2H, m), 2.50-2.80(2H, m), 3.10-4.30 (6H, m), 4.65-5.30 (1H, m), 7.05-7.90 (17H, m),8.30-8.40 (1H, m), 9.10-9.30 (2H, m).

[5400] MS (FAB) m/z: 798 [(M+H)⁺, Cl³⁵], 800 [(M+H)⁺, Cl³⁷].

Example A-2892-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(2-hydroxyethyl)piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5401] In the same manner as in Example A-274, the title compound wasobtained.

[5402]¹H-NMR (CDCl₃) δ: 1.80-2.05 (1H, m), 2.25-2.45 (1H, m), 2.60-2.95(2H, m), 3.00-4.20 (7H, m), 4.70-5.10 (1H, m), 7.40-7.55 (4H, m),7.70-7.90 (3H, m), 8.30-8.40 (1H, m), 9.30 (2H, s).

[5403] MS (FAB) m/z: 560 [(M+H)⁺, Cl³⁵], 562 [(M+H)⁺, Cl³⁷].

Example A-2902-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(pyrrolidin-1-yl)carbonyl]methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5404] In the same manner as in Example A-267, the title compound wasobtained.

[5405]¹H-NMR (DMSO-d₆) δ: 1.70-1.90 (4H, m), 2.30-4.20 (12H, m),4.50-5.20 (1H, m), 7.45-7.65 (3H, m), 7.85-7.90 (1H, m), 8.05-8.15 (2H,m), 8.34 (1H, s), 8.43 (1H, d, J=6.3 Hz), 9.35 (2H, s).

[5406] MS (FAB) m/z: 627 [(M+H)⁺, Cl³⁵], 629 [(M+H)⁺, Cl³⁷].

Example A-2912-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5407] In the same manner as in Example A-267, the title compound wasobtained.

[5408]¹H-NMR (DMSO-d₆) δ: 2.30-2.90 (5H, m), 3.15-4.25 (6H, m),4.50-5.20 (1H, m), 7.45-7.60 (3H, m), 7.85-8.00 (1H, m), 8.05-8.15 (2H,m), 8.34 (1H, s), 8.43 (1H, d, J=6.3 Hz), 9.35 (2H, d, J=4.9 Hz)

[5409] MS (FAB) m/z: 587 [(M+H)⁺, Cl³⁵], 589 [(M+H)⁺, Cl³⁷].

Example A-2922-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(thiomorpholin-4-yl)carbonyl]methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5410] In the same manner as in Example A-267, the title compound wasobtained.

[5411]¹H-NMR (CDCl₃) δ: 2.50-2.90 (7H, m), 3.10-4.85 (9H, m), 4.45-5.45(1H, m), 7.35-7.55 (4H, m), 7.75-7.90 (3H, m), 8.30-8.40 (1H, m), 9.30(2H, d, J=10.5 Hz).

[5412] MS (FAB) m/z: 659 [(M+H)⁺, Cl³⁵], 661 [(M+H)⁺, Cl³⁷].

Example A-2932-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[(N-cyclopropylcarbamoyl)methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5413] In the same manner as in Example A-267, the title compound wasobtained.

[5414]¹H-NMR (CDCl₃) δ: 0.50-0.90 (4H, m), 2.60-6.20 (11H, m), 7.35-7.55(4H, m), 7.70-7.90 (3H, m), 8.30-8.40 (1H, m), 9.25-9.35 (2H, m).

[5415] MS (FAB) m/z: 613 [(M+H)⁺, Cl³⁵], 615 [(M+H)⁺, Cl³⁷].

Example A-2942-[2-[[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5416] In the same manner as in Example A-267, the title compound wasobtained.

[5417]¹H-NMR (CDCl₃) δ: 2.55-2.85 (4H, m), 3.10-5.45 (13H, m), 7.35-7.55(4H, m), 7.70-7.90 (3H, m), 8.30-8.40 (1H, m), 9.25-9.35 (2H, m).

[5418] MS (FAB) m/z: 643 [(M+H)⁺, Cl³⁵], 645 [(M+H)⁺, Cl³⁷].

Example A-2952-[2-[[2-[(N-Benzylcarbamoyl)methyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyrimidin-5-yl]pyridineN-Oxide

[5419] In the same manner as in Example A-267, the title compound wasobtained.

[5420]¹H-NMR (CDCl₃) δ: 2.65-2.85 (3H, m), 2.95-5.45 (8H, m), 6.10-6.30(1H, m), 7.25-7.55 (9H, m), 7.70-7.90 (3H, m), 8.30-8.40 (1H, m),9.25-9.30 (2H, m).

[5421] MS (FAB) m/z: 663 [(M+H)⁺, Cl³⁵], 665 [(M+H)⁺, Cl³⁷].

Example A-2961-[(5-Chloroindol-2-yl)sulfonyl]-4-[4-methyl-2-(pyridin-4-yl)thiazol-5-yl]piperazine

[5422] In the same manner as in Example A-4, the title compound wasobtained.

[5423]¹H-NMR (DMSO-d₆) δ: 2.35 (3H, s), 3.00-3.15 (4H, br), 3.55-3.73(4H, br), 7.01 (1H, s), 7.30 (1H, dd, J=8.8, 2.2 Hz), 7.49 (1H, d, J=8.8Hz), 7.765 (1H, d, J=2.0 Hz), 7.82 (2H, d, J=6.2 Hz), 8.69 (2H, d, J=6.2Hz).

[5424] MS (FAB) m/z: 502 [(M+H)⁺, Cl³⁵], 504 [(M+H)⁺, Cl³⁷].

Example A-2974-[(5-Chloroidol-2-yl)sulfonyl]-1-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]-2-[(pyrrolidin-1-yl)carbonylmethyl]piperazine

[5425] In the same manner as in Example A-66, the title compound wasobtained.

[5426]¹H-NMR (CDCl₃) δ: 1.85-2.05 (4H, m), 2.50-3.30 (5H, m), 3.40-3.60(4H, m), 3.81, 3.90, 4.03, 4.23, 4.64, 5.62 (3H, each br d, J=12.5 Hz),5.15-6.21 (1H, m), 6.99 (1H, s), 7.25-7.50 (4H, m), 7.64 (1H, d, J=5.6Hz), 8.60-8.70 (3H, m), 10.38, 10.95 (1H, each s).

[5427] FAB-MS m/z: 599 [(M+H)⁺, Cl³⁵], 601 [(M+H)⁺, Cl³⁷].

Example A-2984-[2-[[4-[(5-Chloroidol-2-yl)sulfonyl]-2-[(pyrrolidin-1-yl)carbonylmethyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5428] In the same manner as in Example A-4, the title compound wasobtained.

[5429]¹H-NMR (DMSO-d₆) δ: 1.65-1.90 (4H, m), 2.30-3.50 (9H, m),3.50-3.88 (2H, m), 4.41, 5.40 (1H, each br d, J=12.5 Hz), 5.02-5.95 (1H,m), 7.02 (1H, s), 7.31 (1H, dd, J=8.8, 2.0 Hz), 7.48 (1H, d, J=8.8 Hz),7.75-7.83 (3H, m), 8.26 (2H, d, J=7.1 Hz), 8.45, 8.49 (1H, each s),12.42 (1H, br s).

[5430] MS (FAB) m/z: 615 [(M+H)⁺, Cl³⁵], 617 [(M+H)⁺, Cl³⁷].

Example A-2992-[(N-Benzylcarbamoyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[[5-(pyridin-4-yl)thiazol-2-yl]carbonyl]piperazine

[5431] In the same manner as in Example A-66, the title compound wasobtained.

[5432]¹H-NMR (CDCl₃) δ: 2.60-3.06 (4H, m), 3.12-3.57 (1H, m)., 3.78-3.95(1H, m), 3.98-4.12 (1H, m), 4.38-4.56 (2H, m), 4.57-6.01 (2H, m), 6.47,6.58 (1H, each br s), 6.97 (1H, s), 7.25-7.52 (8H, m), 7.65 (2H, d,J=6.6 Hz), 8.64-8.71 (3H, m), 10.24 (1H, s).

[5433] FAB-MS m/z: 635 [(M+H)⁺, Cl³⁵], 637 [(M+H)⁺, Cl³⁷].

Example A-3004-[2-[[2-(N-Benzylcarbamoyl)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazol-5-yl]pyridineN-Oxide

[5434] In the same manner as in Example A-4, the title compound wasobtained.

[5435]¹H-NMR (DMSO-d₆) δ: 2.30-2.92 (3H, m), 3.20-3.63 (2H, m),3.65-3.85 (2H, m), 4.15-4.35 (2H, m), 4.41, 5.41 (1H, each br d, J=13.5Hz), 5.15, 5.98 (1H, each br s), 7.02 (1H, s), 7.15-7.33 (6H, m), 7.48(1H, d, J=8.6 Hz), 7.73-7.81 (3H, m), 8.26 (2H, d, J=6.6 Hz), 8.38-8.60(2H, m), 12.41 (1H, br s).

[5436] MS (FAB) m/z: 651 [(M+H)⁺, Cl³⁵], 653 [(M+H)⁺, Cl³⁷].

Example A-3011-[4-[2-(2-Aminoethyl)pyridin-4-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[5437] In the same manner as in Example A-7, the title compound wasobtained.

[5438]¹H-NMR (DMSO-d₆) δ: 3.08 (4H, s), 3.23 (2H, br), 3.30 (2H, br),3.45 (2H, br), 3.73 (2H, br), 7.52 (2H, d, J=8.3 Hz), 7.74 (1H, dd,J=5.4, 2.0 Hz), 7.80-7.87 (5H, m), 8.06 (2H, br), 8.19 (1H, d, J=8.8Hz), 8.25-8.31 (2H, m), 8.51 (1H, br s), 8.69 (1H, d, J=4.4 Hz)

[5439] MS (FAB) m/z: 535 [(M+H)⁺, Cl³⁵], 537 [(M+H)⁺, Cl³⁷].

[5440] Elementary analysis for C₂₈H₂₇ClN₄O₃S.1.85HCl.1.4H₂O

[5441] Calculated: C, 53.57; H, 5.08; Cl, 16.10; N, 8.93; S, 5.11.

[5442] Found: C, 53.39; H, 5.06; Cl, 15.99; N, 8.81; S, 5.08.

Example A-3021-[[5(6)-Chloroimidazol-2-yl]sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazineHydrochloride

[5443] 1-[[5(6)-Chlorobenzimidazol-2-yl]sulfonyl]piperazine (507 mg),1-hydroxybenzotriazole (220 mg), N-methylmorpholine (480 μl) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (309 mg) weresuccessively added to the mixture of 4-[(pyridin-4-yl)benzoic acid (314mg), dichloromethane (5.0 ml) and N,N-dimethylformamide (2.0 ml),stirred at room temperature for 5 hours. The mixture was diluted withdichloromethane, and then divided into two layers by adding a saturatedsodium chloride solution. The organic layer was washed with a saturatedsodium chloride solution, dried over sodium sulfate, and concentratedunder reduced pressure. The obtained product was purified bychromatography on a silica gel column (dichloromethane:methanol=15:1).After dichloromethane was removed from the mixture of dichloromethaneand methanol under reduced pressure,1-[[5(6)-chloroimidazol-2-yl]sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine(396 mg) was obtained as precipitated powder by filtration. 140 mg ofthis obtained compound was concentrated by adding 1N aqueoushydrochloride in ethanol (3 ml) and ethanol (3 ml), and dried, wherebythe title compound (152 mg) was obtained as colorless amorphous.

[5444] IR (KBr) cm⁻¹ 1631, 1431, 1365, 1282, 1155.

[5445]¹H-NMR (DMSO-d₆) δ, 3.30-4.00 (8H, br), 7.43 (1H, d, J=8.8, 2.0Hz), 7.62 (2H, d, J=7.8 Hz), 7.75 (1H, d, J=8.8 Hz), 7.80 (1H, s), 8.07(2H, d, J=8.8 Hz), 8.38 (2H, d, J=5.9 Hz), 8.97 (2H, d, J=5.9 Hz).

[5446] MS (FAB) m/z 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

Example A-3034-[4-[[5(6)-chlorobenzimidazol-2-yl]sufonyl]piperazin-1-yl]carbonylphenyl]piridineN-Oxide

[5447] Metachloroperbenzoic acid (0° C.; 121 mg) was added to themixture of1-[[5(6)-chloroimidazol-2-yl]sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine(191 mg) obtained by Example A-302, N,N-dimethylformamide (5.0 ml) andchloroform (15 ml) at a temperature of 0° C., and stirred at atemperature of 0° C. for 3 hours, thereto was added dichloromethane (50ml), followed by stirring at room temperature for 64 hours. The mixturewas divided into two layers by adding a small quantity of sodiumthiosulfate solution, and saturated sodium chloride solution. Theorganic layer was washed with a saturated sodium hydrogencarbonatesolution and a saturated sodium chloride solution, dried over sodiumsulfate, and concentrated under reduced pressure. The obtained productwas purified by chromatography on a silica gel column(dichloromethane:methanol=20:1). The mixture of dichloromethane andmethanol was concentrated under reduced pressure, filtered and dried toobtain solid. Thus, the title compound (141 mg) was obtained ascolorless amorphous.

[5448] IR (KBr) cm⁻¹ 1645, 1433, 1371, 1248, 1180, 966, 933.

[5449]¹H-NMR (DMSO-d₆) 6, 3.30-3.85 (8H, br), 7.41 (1H, dd, J=8.8, 2.0Hz), 7.49 (2H, d, J=7.8 Hz), 7.68-7.83 (2H, br), 7.80 (2H, d, J=6.8 Hz),7.83 (2H, d, J=7.8 Hz), 8.27 (2H, d, J=6.8 Hz).

[5450] MS (FAB) m/z 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

Example B-11-[[(6RS)-6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5451] In saturated aqueous hydrochloric acid in ethanol (5 ml),1-[[(6RS)-6-(N-tert-butoxycarbonylaminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(0.22 g) was dissolved, followed by stirring at room temperature for 90minutes. The residue obtained by distilling off the solvent underreduced pressure was recrystallized from a mixed solvent of ethanol anddiethyl ether, whereby the title compound (0.14 g, 68%) was obtained.

[5452]¹H-NMR (DMSO-d₆) δ: 1.30-1.50 (1H, m), 1.90-2.10 (2H, m),2.40-2.60 (1H, m), 2.60-3.00 (5H, m), 3.03 (4H, m), 3.40-3.80 (4H, br),7.00-7.10 (3H, m), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, dd, J=8.8,1.5 Hz), 8.05 (3H, br), 8.18 (1H, d, J=8.3 Hz), 8.20-8.30 (2H, m), 8.49(1H, s).

[5453] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[5454] Elementary analysis for C₂₆H₂₈ClN₃O₃S.HCl.{fraction (3/2)}H₂O

[5455] Calculated: C, 55.61; H, 5.74; N, 7.48; Cl, 12.63; S, 5.71.

[5456] Found: C, 55.64; H, 5.53; N, 7.77; Cl, 12.79; S, 5.76.

Example B-21-[[(6RS)-6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5457] In the same manner as in Example B-1, the title compound wasobtained using1-[[(6RS)-6-(N-tert-butoxycarbonylaminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5458]¹H-NMR (DMSO-d₆) δ: 1.30-1.50 (1H, m), 2.00-2.10 (2H, m),2.40-2.60 (1H, m), 2.60-3.00 (7H, m), 3.00-3.20 (2H, m), 3.30-3.50 (2H,m), 3.82 (2H, m), 4.22 (2H, br), 7.00-7.10 (1H, m), 7.25 (2H, s), 7.73(1H, dd, J=8.8, 2.4 Hz), 7.81 (1H, dd, J=8.8, 1.5 Hz), 8.00-8.40 (6H,m), 8.52 (1H, s), 11.08 (1H, br)

[5459] MS (FAB) m/z: 484[(M+H)⁺, Cl³⁵], 486[(M+H)⁺, Cl³⁷].

[5460] Elementary analysis for C₂₆H₃₀ClN₃O₂S.2HCl

[5461] Calculated: C, 56.07; H, 5.79; N, 7.54; Cl, 19.10; S, 5.76.

[5462] Found: C, 56.04; H, 5.79; N, 7.52; Cl, 18.95; S, 5.80.

Example B-31-[[(2RS)-6-Aminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5463] In the same manner as in Example B-1, the title compound wasobtained using1-[[(2RS)-6-(N-tert-butoxycarbonylaminomethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5464]¹H-NMR (DMSO-d₆) δ: 1.30-1.50 (1H, m), 2.00-2.20 (1H, m),2.20-2.40 (1H, m), 2.40-2.60 (1H, m), 2.75 (2H, m), 2.90-3.30 (7H, m),3.60-3.70 (2H, m), 3.70-4.00 (4H, m), 7.04 (1H, d, J=7.8 Hz), 7.10-7.30(2H, m), 7.74 (1H, m), 7.86 (1H, d, J=8.8 Hz), 8.20-8.50 (6H, m), 8.56(1H, s), 10.69 (1H, br).

[5465] MS (FAB) m/z: 484 [(M+H)⁺, Cl³⁵], 486 [(M+H)⁺, Cl³⁷].

[5466] Elementary analysis for C₂₆H₃₀ClN₃O₂S.2HCl.½H₂O

[5467] Calculated: C, 55.18; H, 5.88; N, 7.42; Cl, 18.79; S, 5.66.

[5468] Found: C, 55.34; H, 5.70; N, 7.31; Cl, 18.76; S, 5.85.

Example B-41-[[(2RS)-6-Aminomethyl-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5469] In the same manner as in Example B-1, the title compound wasobtained using1-[[(2RS)-6-(N-tert-butoxycarbonylaminomethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5470]¹H-NMR (DMSO-d₆) δ: 1.55 (1H, m), 1.80-1.90 (1H, m), 2.60-2.90(4H, m), 2.90-3.10 (5H, m), 3.50-3.80 (4H, m), 3.90 (2H, s), 7.05 (1H,d, J=7.8 Hz), 7.10-7.20 (2H, m), 7.71 (1H, d, J=8.8 Hz), 7.82 (1H, d,J=8.3 Hz), 8.10-8.40 (6H, m), 8.50 (1H, s).

[5471] MS (FAB) m/z: 498 [(M+H)⁺, Cl³⁵], 500 [(M+H)⁺, Cl³⁷].

[5472] Elementary analysis for C₂₆H₂₈ClN₃O₃S.1.2HCl.0.8H₂O

[5473] Calculated: C, 56.15; H, 5.58; N, 7.55; Cl, 14.02; S, 5.76.

[5474] Found: C, 55.93; H, 5.22; N, 7.37; Cl, 14.26; S, 5.70.

Example B-51-[(7-Aminomethylnaphthalen-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5475] In the same manner as in Example B-1, the title compound wasobtained using1-[[7-(N-tert-butoxycarbonylaminomethyl)naphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5476]¹H-NMR (DMSO-d₆) δ: 3.10 (4H, br), 3.30-3.90 (4H, br), 4.18 (2H,s), 7.46 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=8.8 Hz), 7.73 (1H, d, J=8.8Hz), 7.83 (1H, d, J=8.8 Hz), 7.89 (1H, s), 7.90-8.00 (3H, m), 8.19 (1H,d, J=8.8 Hz), 8.20-8.30 (2H, m), 8.50 (4H, br s).

[5477] MS (FAB) m/z: 494 [(M+H)⁺, Cl³⁵], 496 [(M+H)⁺, Cl³⁷].

[5478] Elementary analysis for C₂₆H₂₄ClN₃O₃S.HCl.¾H₂O

[5479] Calculated: C, 57.41; H, 4.91; N, 7.72; Cl, 13.03; S, 5.89.

[5480] Found: C, 57.40; H, 4.87; N, 7.71; Cl, 13.09; S, 5.89.

Example B-61-[(7-Aminomethylnaphthalen-2-yl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5481] In the same manner as in Example B-1, the title compound wasobtained using1-[[7-(N-tert-butoxycarbonylaminomethyl)naphthalen-2-yl]methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5482]¹H-NMR (DMSO-d₆) δ: 2.92 (2H, m), 3.22 (2H, m), 3.83 (2H, m), 4.20(2H, d, J=5.4 Hz), 4.51 (2H, br), 7.60-7.90 (4H, m), 7.90-8.40 (7H, m),8.52 (1H, s), 8.57 (3H, br), 11.52 (1H, br).

[5483] MS (FAB) m/z: 480 [(M+H)⁺, Cl³⁵], 482 [(M+H)⁺, Cl³⁷].

[5484] Elementary analysis for C₂₆H₂₆ClN₃O₂S.2HCl.¼H₂O

[5485] Calculated: C, 56.02; H, 5.15; N, 7.54; Cl, 19.08; S, 5.75.

[5486] Found: C, 55.88; H, 5.45; N, 7.34; Cl, 18.90; S, 5.69.

Example B-71-[(6-Aminomethylnaphthalen-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5487] In tetrahydrofuran (5 ml),2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonylnaphthalene (0.15g) was dissolved, followed by the addition of 1N sodium hydroxide (0.70ml). The resulting mixture was stirred at room temperature for 16 hours.After the reaction mixture was concentrated under reduced pressure, theconcentrate was diluted with dichloromethane and added with dilutehydrochloric acid to separate the organic layer. The organic layer thusobtained was dried over anhydrous sodium sulfate. The residue obtainedby distilling off the solvent under reduced pressure was dissolved inN,N-dimethylformamide (5 ml), followed by the addition of1-[(6-chloronaphthalen-2-yl) sulfonyl]piperazine hydrochloride (0.21 g),N-methylmorpholine (54.0 μl),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94.0 mg)and 1-hydroxybenzotriazole (77.0 mg). The resulting mixture was stirredat room temperature for 21 hours. The reaction mixture was concentratedunder reduced pressure. The concentrate was diluted with ethyl acetate,washed with water and dried over anhydrous sodium sulfate. The residueobtained by distilling off the solvent under reduced pressure waspurified by chromatography on a silica gel column(dichloromethane˜dichloromethane:methanol=100:1), followed by thereaction in the same manner as in Example B-1, whereby the titlecompound (77.0 g, 29%) was obtained as colorless crystals.

[5488]¹H-NMR (DMSO-d₆) δ: 3.09 (4H, br), 3.40-3.90 (4H, br), 4.19 (2H,s), 7.47 (1H, d, J=8.3 Hz), 7.66 (1H, d, J=8.3 Hz), 7.73 (1H, d, J=9.3Hz), 7.83 (1H, d, J=8.8 Hz), 7.90-8.10 (4H, m), 8.19 (1H, d, J=8.8 Hz),8.20-8.30 (2H, m), 8.40-8.60 (4H, m).

[5489] MS (FAB) m/z: 494 [(M+H)⁺, Cl³⁵], 496 [(M+H)⁺, Cl³⁷].

[5490] Elementary analysis for C₂₆H₂₄ClN₃O₃S.HCl.¾H₂O.⅕Et₂O

[5491] Calculated: C, 57.60; H, 5.14; N, 7.52; Cl, 12.69; S, 5.74.

[5492] Found: C, 57.64; H, 5.10; N, 7.12; Cl, 12.69; S, 5.82.

Example B-81-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(isoquinolin-7-yl)carbonyl]piperazineHydrochloride

[5493] In 4N hydrochloric acid, methyl 7-isoquinolinecarboxylate (J.Org. Chem., 38(21), 3701, 1973) (206 mg) was dissolved, followed byheating under reflux for 4 hours. In the same manner as in Example B-7,a reaction was effected using the residue obtained by distilling off thesolvent under reduced pressure and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials, whereby the title compound (298 mg, 62%) wasobtained.

[5494]¹H-NMR (DMSO-d₆) δ: 2.95-3.25 (4H, m), 3.40-3.60 (2H, m),3.70-3.90 (2H, m), 7.73 (1H, dd, J=8.8, 2.0 Hz), 7.84 (1H, d, J=8.8 Hz),8.05 (1H, d, J=7.3 Hz), 8.20 (1H, d, J=8.8 Hz), 8.25-8.35 (3H, m), 8.41(1H, d, J=6.4 Hz), 8.45 (1H, s), 8.52 (1H, s), 8.71 (1H, d, J=6.4 Hz),9.79 (1H, s).

[5495] MS (FAB) m/z: 465 [(M+H)⁺, Cl³⁵), 467 [(M+H)⁺, Cl³⁷].

[5496] Elementary analysis for C₂₄H₂₀ClN₃O₃S.HCl.2.2H₂O

[5497] Calculated: C, 53.18; H, 4.72; N, 7.75; Cl, 13.08; S, 5.92.

[5498] Found: C, 53.11; H, 4.70; N, 7.60; Cl, 13.01; S, 6.16.

Example B-91-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(quinolyl-2-yl)carbonyl]piperazineHydrochloride

[5499] In the same manner as in Example B-7, the title compound wasobtained using quinoline-2-carboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[5500]¹H-NMR (DMSO-d₆) δ: 3.05 (2H, m), 3.17 (2H, m), 3.62 (2H, m), 3.83(2H, m), 7.61 (1H, d, J=8.3 Hz), 7.60-7.80 (2H, m), 7.80-7.90 (2H, m),7.95 (1H, d, J=8.3 Hz), 8.00 (1H, d, J=7.3 Hz), 8.18 (1H, d, J=8.8 Hz),8.20-8.40 (2H, m), 8.43 (1H, d, J=8.3 Hz), 8.51 (1H, s).

[5501] Elementary analysis for C₂₄H₂₀ClN₃O₃S

[5502] Calculated: C, 61.87; H, 4.33; N, 9.02; Cl, 7.61; S, 6.88.

[5503] Found: C, 61.76; H, 4.20; N, 8.73; Cl, 7.65; S, 6.99.

Example B-101-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4-hydroxyquinolin-2-yl)carbonyl]piperazineHydrochloride

[5504] In the same manner as in Example B-7, the title compound wasobtained using 4-hydroxyquionoline-2-carboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[5505]¹H-NMR (DMSO-d₆) δ: 3.00-3.30 (4H, br), 3.53 (2H, br), 3.77 (2H,br), 6.45 (1H, s), 7.48 (1H, t, J=7.3 Hz), 7.70-7.90 (4H, m), 8.10-8.40(4H, m), 8.52 (1H, s).

[5506] MS (FAB) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

[5507] Elementary analysis for C₂₄H₂₀ClN₃O₄S.{fraction(9/10)}HCl.⅓CH₃OH, {fraction (3/2)}H₂O

[5508] Calculated: C, 52.90; H, 4.60; N, 7.61; Cl, 12.19; S, 5.80.

[5509] Found: C, 53.17; H, 4.59; N, 7.39; Cl, 12.31; S, 6.07.

Example B-111-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(8-hydroxyquinolin-7-yl)carbonyl]piperazineHydrochloride

[5510] In the same manner as in Example B-7, the title compound wasobtained using 8-hydroxyquionoline-7-carboxylic acid and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[5511]¹H-NMR (DMSO-d₆) δ: 2.90-3.30 (4H, br), 3.35 (2H, br), 3.79 (2H,br), 7.39 (1H, d, J=8.3 Hz), 7.53 (1H, d, J=8.3 Hz), 7.60-7.90 (3H, m),8.10-8.40 (3H, m), 8.50 (1H, s), 8.60 (1H, d, J=7.8 Hz), 8.96 (1H, d,J=4.4 Hz).

[5512] MS (FAB) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

[5513] Elementary analysis for C₂₄H₂₀ClN₃O₄S.HCl.CH₃OH.¼H₂O

[5514] Calculated: C, 54.11; H, 4.63; N, 7.57; Cl, 12.78; S, 5.78.

[5515] Found: C, 54.40; H, 4.84; N, 7.66; Cl, 13.04; S, 5.99.

Example B-121-[(Benzimidazol-5-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineHydrochloride

[5516] In the same manner as in Example B-7, the title compound wasobtained using methyl N-triphenylmethyl-5-benzimidazolecarboxylate and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[5517]¹H-NMR (DMSO-d₆) δ: 3.08 (4H, br), 3.30-4.00 (4H, br), 7.48 (1H,d, J=8.3 Hz), 7.60-7.90 (4H, m), 8.10-8.30 (3H, m), 8.50 (1H, s), 9.51(1H, s).

[5518] MS (FAB) m/z: 455 [(M+H)⁺, Cl³⁵], 457 [(M+H)⁺, Cl³⁷].

[5519] Elementary analysis for C₂₂H₁₉ClN₄O₃S.HCl.{fraction (5/4)}H₂O

[5520] Calculated: C, 51.42; H, 4.41; N, 10.90; Cl, 13.80; S, 6.24.

[5521] Found: C, 51.53; H, 4.40; N, 10.71; Cl, 13.61; S, 6.40.

Example B-131-[(Benzimidazol-5-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazineHydrochloride

[5522] In the same manner as in Example B-12, the title compound wasobtained using methyl N-triphenylmethyl-5-benzimidazolecarboxylate and1-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine hydrochloride asstarting materials.

[5523]¹H-NMR (DMSO-d₆) δ: 1.67 (1H, m), 1.93 (1H, m), 3.20-3.90 (8H, m),7.44 (½H, m), 7.54 (½H, m), 7.68 (1H, m), 7.80-8.00 (3H, m), 8.10-8.30(3H, m), 8.49 (½H, s), 8.55 (½H, s), 9.56 and 9.57 (1H, each s).

[5524] MS (FAB) m/z: 469 [(M+H)⁺, Cl³⁵], 471 [(M+H)⁺, Cl³⁷].

[5525] Elementary analysis for C₂₃H₂₁ClN₄O₃S.HCl.0.3CH₃OH.H₂O

[5526] Calculated: C, 52.50; H, 4.76; N, 10.51; Cl, 13.30; S, 6.01.

[5527] Found: C, 52.31; H, 4.66; N, 10.50; Cl, 13.34; S, 6.01.

Example B-141-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5528] In the same manner as in Example B-7, the title compound wasobtained using sodium thiazolo[5,4-c]pyridine-2-carboxylate and1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride asstarting materials.

[5529]¹H-NMR (DMSO-d₆) δ: 3.10-3.30 (4H, m), 3.84 (2H, m), 4.32 (2H, m),7.69 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.10-8.30(4H, m), 8.51 (1H, s), 8.79 (1H, d, J=5.9 Hz), 9.62 (1H, s).

[5530] MS (FAB) m/z: 473 [(M+H)⁺, Cl³⁵], 475 [(M+H)⁺, Cl³⁷].

[5531] Elementary analysis for C₂₁H₁₇ClN₄O₃S₂ HCl

[5532] Calculated: C, 49.51; H, 3.56; N, 11.00; Cl, 13.92; S, 12.59.

[5533] Found: C, 49.45; H, 3.71; N, 11.20; Cl, 13.67; S, 12.55.

Example B-151-[(E)-4-Chlorostyrylsulfonyl]-4-[(thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5534] In the same manner as in Example B-7, the title compound wasobtained using sodium thiazolo[5,4-c]pyridine-2-carboxylate and1-[(E)-4-chlorostyrylsulfonyl]piperazine hydrochloride as startingmaterials.

[5535]¹H-NMR (DMSO-d₆) δ: 3.30 (4H, m), 3.87 (2H, m), 4.35 (2H, m), 7.35(1H, d, J=15.6 Hz), 7.40-7.50 (3H, m), 7.79 (1H, d, J=8.3 Hz), 8.22 (1H,d, J=5.9 Hz), 8.77 (1H, d, J=5.9 Hz), 9.59 (1H, s).

[5536] MS (FAB) m/z: 449 [(M+H)⁺, Cl³⁵], 451 [(M+H)⁺, Cl³⁷].

[5537] Elementary analysis for C₁₉H₁₇ClN₄O₃S₂.½HCl

[5538] Calculated: C, 48.85; H, 3.78; N, 11.99; Cl, 11.38; S, 13.73.

[5539] Found: C, 49.18; H, 3.80; N, 12.20; Cl, 11.05; S, 13.84.

Example B-161-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]piperazineHydrochloride

[5540] In the same manner as in Example B-1, the title compound wasobtained using1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5541]¹H-NMR (DMSO-d₆) δ: 2.82-2.88 (4H, m), 2.91-2.99 (4H, m),3.28-3.36 (2H, m), 3.47-3.55 (4H, m), 4.02 (2H, br s), 6.58 (1H, s),7.71 (1H, dd, J=8.8, 2.0 Hz), 7.81 (1H, dd, J=8.8, 2.0 Hz), 7.23-7.28(3H, m), 8.49 (1H, s), 9.42 (2H, br s).

[5542] MS (FAB) m/z: 462 [(M+H)⁺, Cl³⁵], 464 [(M+H)⁺, Cl³⁷].

Example B-171-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[trans-3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propenoyl]piperazineHydrochloride

[5543] In the same manner as in Example B-1, the title compound wasobtained using1-[trans-3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propenoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5544]¹H-NMR (DMSO-d₆) δ: 2.95-3.10 (6H, m), 3.32-3.51 (3H, m),3.60-3.80 (3H, m), 4.12 (2H, s), 6.75 (1H, d, J=15.1 Hz), 7.19 (1H, s),7.50 (1H, d, J=15.1 Hz), 7.70 (1H, dd, J=8.8, 2.4 Hz), 7.81 (1H, dd,J=8.8, 2.0 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=2.0 Hz), 8.50(1H, s), 9.53 (2H, br s).

[5545] MS (FAB) m/z: 502 [(M+H)⁺, Cl³⁵], 504 [(M+H)⁺, Cl³⁷].

[5546] Elementary analysis for C₂₄H₂₄ClN₃O₃S₂.HCl.0.5H₂O

[5547] Calculated: C, 52.65; H, 4.79; Cl, 12.95; N, 7.67; S, 11.71.

[5548] Found: C, 52.36; H, 4.88; Cl, 12.63; N, 8.01; S, 11.39.

Example B-181-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propionyl]piperazineHydrochloride

[5549] In the same manner as in Example B-1, the title compound wasobtained using1-[3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propionyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5550]¹H-NMR (DMSO-d₆) δ: 2.80-3.60 (16H, m), 4.12 (2H, br s), 7.11 (1H,br s), 7.74 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.20(1H, s), 8.25-8.30 (2H, m), 8.53 (1H, s), 9.67 (2H, br s).

[5551] MS (FAB) m/z: 504 [(M+H)⁺, Cl³⁵], 506 [(M+H)⁺, Cl³⁷].

[5552] Elementary analysis for C₂₄H₂₆ClN₃O₃S₂.1.2HCl.1.3H₂O

[5553] Calculated: C, 50.46; H, 5.26; Cl, 13.65; N, 7.36.

[5554] Found: C, 50.83; H, 5.26; Cl, 13.43; N, 6.97.

Example B-191-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propyl]piperazineHydrochloride

[5555] In the same manner as in Example B-1, the title compound wasobtained using1-[3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5556]¹H-NMR (DMSO-d₆) δ: 1.90-2.07 (2H, m), 2.72-2.80 (2H, m),2.82-3.21 (8H, m), 3.35 (2H, br s), 3.51 (2H, d, J=11.5 Hz), 3.82 (2H,d, J=11.5 Hz), 4.06 (2H, s), 6.66 (1H, s), 7.74 (1H, dd, J=8.8, 1.5 Hz),7.85 (1H, dd, J=8.8, 1.5 Hz), 8.20 (1H, d, J=8.8 Hz), 8.25-8.39 (2H, m),8.55 (1H, s), 9.50 (2H, br s), 11.26 (1H, br s).

[5557] MS (FAB) m/z: 490 [(M+H)⁺, Cl³⁵], 492 [(M+H)⁺, Cl³⁷].

[5558] Elementary analysis for C₂₄H₂₈ClN₃O₂S₂.2HCl.1.6H₂O

[5559] Calculated: C, 48.71; H, 5.65; Cl, 17.97; N, 7.10; S, 10.84.

[5560] Found: C, 49.01; H, 5.77; Cl, 17.62; N, 6.96; S, 10.82.

Example B-201-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[N-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]carbamoyl]piperazineHydrochloride

[5561] In the same manner as in Example B-1, the title compound wasobtained using1-[N-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5562]¹H-NMR (DMSO-d₆) δ: 2.78-2.86 (2H, br s), 2.88-2.94 (4H, m),3.29-3.35 (2H, m), 3.37-3.42 (4H, m), 4.03 (2H, br s), 4.19 (2H, d,J=5.4 Hz), 6.62 (1H, s), 7.25 (1H, t, J=5.4 Hz), 7.72 (1H, dd, J=8.8,2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.16 (1H, d, J=8.8 Hz), 8.22-8.26(2H, m), 8.50 (1H, s), 9.27 (2H, br s).

[5563] Elementary analysis for C₂₃H₂₅ClN₄O₃S₂.HCl.1.3H₂O

[5564] Calculated: C, 48.90; H, 5.10; Cl, 12.55; N, 9.92.

[5565] Found: C, 49.02; H, 5.20; Cl, 12.50; N, 9.76.

Example B-211-[(6-Chloronaphthalen-2-yl)sulfonyl)-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5566] In the same manner as in Example B-1, the title compound wasobtained using1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5567]¹H-NMR (DMSO-d₆) δ: 2.99-3.05 (2H, m), 3.08 (4H, t, J=4.6 Hz),3.35-3.40 (2H, m), 3.71 (4H, t, J=4.6 Hz), 4.11 (2H, s), 7.17 (1H, s),7.71 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.22-8.28(3H, m), 8.50 (1H, s), 9.38 (2H, br s).

[5568] MS (FAB) m/z: 476 [(M+H)⁺, Cl³⁵], 478 [(M+H)⁺, Cl³⁷].

[5569] Elementary analysis for C₂₂H₂₃ClN₃O₃S₂.HCl.{fraction (3/2)}H₂O

[5570] Calculated: C, 48.98; H, 4.86; Cl, 13.14; N, 7.79; S, 11.89.

[5571] Found: C, 48.96; H, 4.67; Cl, 13.21; N, 7.74; S, 11.93.

Example B-224-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5572] In the same manner as in Example B-1, the title compound wasobtained using1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazineas a starting material.

[5573]¹H-NMR (DMSO-d₆) δ: 1.22 (3H, t, J=7.0 Hz), 2.38-2.58 (1H, m),2.65-2.72 (1H, m), 3.04 (2H, br s), 3.29-3.43 (3H, m), 3.70 (1H, br s),4.01-4.30 (6H, m), 5.18 (1H, br s), 7.27 (1H, s), 7.73 (1H, dd, J=8.8,2.0 Hz), 7.82 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.29 (1H, s), 8.54 (1H,s), 9.59 (2H, br s).

[5574] MS (FAB) m/z: 548 [(M+H)⁺, Cl³⁵], 550 [(M+H)⁺, Cl³⁷].

[5575] Elementary analysis for C₂₅H₂₆N₃ClO₅S₂.1.2HCl.0.6H₂O

[5576] Calculated: C, 49.83; H, 4.75; Cl, 12.94; N, 6.97; S, 10.64.

[5577] Found: C, 49.62; H, 4.71; Cl, 13.30; N, 7.19; S, 10.56.

Example B-232-Carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5578] In tetrahydrofuran (1 ml),4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (95 mg) was dissolved, followed by the addition of ethanol(2 ml) and 1N sodium hydroxide (3 ml). The resulting mixture was heatedunder reflux for 30 minutes. To the reaction mixture, 4N hydrochloricacid (2 ml) was added and the precipitate thus obtained was collected byfiltration, whereby the title compound (83 mg, 90%) was obtained as acolorless foam.

[5579]¹H-NMR (DMSO-d₆) δ: 2.30-2.53 (1H, m), 2.58-2.69 (1H, m), 3.04(2H, br s), 3.29-3.83 (4H, m), 4.07-4.32 (4H, m), 4.90-5.20 (1H, m),7.03-7.30 (1H, m), 7.71 (1H, dd, J=8.8, 2.4 Hz), 7.81 (1H, d, J=8.8 Hz),8.81 (1H, d, J=8.8 Hz), 8.20-8.29 (2H, m), 8.52 (1H, s), 9.58 (2H, brs).

[5580] MS (FAB) m/z: 520 [(M+H)⁺, Cl³⁵], 522 [(M+H)⁺, Cl³⁷].

[5581] Elementary analysis for C₂₃H₂₂N₃ClO₅S₂.1.2HCl.0.8H₂O

[5582] Calculated: C, 47.78; H, 4.32; Cl, 13.49; N, 7.27; S, 11.09.

[5583] Found: C, 47.41; H, 4.36; Cl, 13.81; N, 7.14; S, 11.01.

Example B-241-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine

[5584] To methanol (4 ml), a solution of1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(5-cyano-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine(41 mg) in dichloromethane (1 ml) was added, followed by the addition ofhydroxylamine hydrochloride (28 mg) and triethylamine (0.55 ml). Theresulting mixture was stirred at room temperature for 2 hours. Theresidue obtained by concentrating the reaction mixture under reducedpressure was purified by chromatography on a silica gel column(dichloromethane˜dichloromethane:methanol=100:3), whereby the titlecompound (14 mg, 32%) was obtained.

[5585]¹H-NMR (DMSO-d₆) δ: 2.74-2.79 (2H, m), 3.06 (4H, s), 3.35-3.38(2H, m), 3.71 (4H, s), 4.07 (2H, s), 5.32 (2H, s), 7.08 (1H, s), 7.71(1H, dd, J=8.8, 1.6 Hz), 7.81 (1H, dd, J=8.8, 1.6 Hz), 8.16 (1H, s),8.23-8.25 (2H, m), 8.33 (1H, br s), 8.49 (1H, s).

[5586] MS (FAB) m/z: 534 [(M+H)⁺, Cl³⁵], 536 [(M+H)⁺, Cl³⁷].

Example B-251-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[N-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]piperazineHydrochloride

[5587] In the same manner as in Example B-1, the title compound wasobtained using1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5588]¹H-NMR (DMSO-d₆) δ: 2.83 (2H, br s), 2.99 (4H, br s), 3.30 (2H, brs), 3.54 (4H, br s), 4.00 (2H, s), 6.33 (1H, s), 7.70 (1H, dd, J=8.8,2.0 Hz), 7.82 (1H, d, J=8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.22 (1H, s),8.26 (1H, d, J=8.8 Hz), 8.50 (1H, s), 9.18 (2H, br s), 9.82 (1H, s).

[5589] MS (FAB) m/z: 491 [(M+H)⁺, Cl³⁵], 493 [(M+H)⁺, Cl³⁷].

[5590] Elementary analysis for C₂₂H₂₃N₄ClO₃S₂.HCl.0.3H₂O

[5591] Calculated: C, 49.59; H, 4.65; Cl, 13.31; N, 10.51; S, 12.03.

[5592] Found: C, 49.32; H, 4.63; Cl, 13.34; N, 10.81; S, 12.03.

Example B-261-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[N-methyl-N-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbamoyl]piperazineHydrochloride

[5593] In the same manner as in Example B-1, the title compound wasobtained using1-[N-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N-methylcarbamoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5594]¹H-NMR (DMSO-d₆) δ: 2.83 (2H, d, J=5.4 Hz), 2.97 (4H, br s), 3.10(3H, s), 3.28-3.41 (6H, m), 4.00 (2H, s), 6.35 (1H, s), 7.72 (1H, dd,J=8.8, 2.0 Hz), 7.81 (1H, dd, J=8.8, 2.0 Hz), 8.17 (1H, d, J=8.8 Hz),8.23-8.31 (2H, m), 8.50 (1H, s), 9.28 (2H, br s).

[5595] MS (FAB) m/z: 505 [(M+H)⁺, Cl³⁵], 507 [(M+H)⁺, Cl³⁷].

[5596] Elementary analysis for C₂₃H₂₅N₄ClO₃S₂.1.1HCl.0.5H₂O

[5597] Calculated: C, 49.85; H, 4.93; Cl, 13.43; N, 10.11; S, 11.57.

[5598] Found: C, 49.55; H, 4.92; Cl, 13.23; N, 10.13; S, 11.83.

Example B-271-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(1-pyrrolin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[5599] In N,N-dimethylformamide (20 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (400 mg) was dissolved, followed by the addition oftriethylamine (0.16 ml) and 2-methoxypyrroline (464 mg). The resultingmixture was stirred at room temperature for 3 days. The reaction mixturewas concentrated under reduced pressure. To the residue, 1N hydrochloricacid was added and the precipitate thus formed was collected byfiltration, whereby the title compound (411 mg, 88%) was obtained as apale yellow foamy solid.

[5600]¹H-NMR (DMSO-d₆) δ: 2.07-2.18 (2H, m), 2.90-3.11 (8H, m), 3.62(2H, t, J=6.8 Hz), 3.72 (4H, br), 3.80 (2H, t, J=5.9 Hz), 3.99 (2H, t,J=5.9 Hz), 4.62 (1H, br s), 4.73 (1H, br s), 7.10 (1H, s), 7.50 (1H, s),7.72 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.18 (1H, d,J=8.8 Hz), 8.22-8.28 (2H, m), 8.51 (1H, s), 10.37 (1H, br s), 10.53 (1H,br s).

[5601] MS (FAB) m/z: 542 [(M+H)⁺, Cl³⁵], 544 [(M+H)⁺, Cl³⁷].

[5602] Elementary analysis for C₂₆H₂₇ClN₄O₃S₂.1.3HCl.0.4H₂O

[5603] Calculated: C, 52.25; H, 4.91; Cl, 13.64; N, 9.37; S, 10.73.

[5604] Found: C, 52.34; H, 5.03; Cl, 13.56; N, 9.36; S, 10.74.

Example B-281-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5605] In the same manner as in Example B-1, the title compound wasobtained using1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5606]¹H-NMR (DMSO-d₆) δ: 3.01 (2H, t, J=5.9 Hz), 3.11 (4H, br), 3.44(2H, br s), 3.74 (2H, br s), 4.32-4.46 (4H, m), 7.71 (1H, dd, J=8.8, 2.0Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.15 (1H, d, J=8.8 Hz), 8.23 (1H, s),8.26 (1H, d, J=8.8 Hz), 8.30 (1H, s).

[5607] MS (FAB) m/z: 477 [(M+H)⁺, Cl³⁵], 479 [(M+H)⁺, Cl³⁷].

[5608] Elementary analysis for C₂₁H₂₁ClN₄O₃S₂.HCl.0.2H₂O

[5609] Calculated: C, 48.78; H, 4.37; Cl, 13.71; N, 10.84; S, 12.40.

[5610] Found: C, 48.60; H, 4.50; Cl, 13.58; N, 10.62; S, 12.29.

Example B-291-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride; and1-[(6-carbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine

[5611] In a similar manner to Referential Example 33 and Example B-24 byusing1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride as a starting material,1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride and also1-[(6-carbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazinewere obtained.1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride:

[5612]¹H-NMR (DMSO-d₆) δ: 2.77 (2H, br s), 3.09 (4H, br), 3.48 (2H, t,J=5.4 Hz), 3.73 (2H, br s), 4.30-4.50 (4H, m), 5.61 (1H, br s), 7.71(1H, dd, J=8.8 Hz, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.15 (1H, d,J=8.8 Hz), 8.22 (1H, d, J=1.5 Hz), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, s),8.53 (1H, br s).

[5613] MS (FAB) m/z: 535 [(M+H)⁺, Cl³⁵], 537 [(M+H)⁺, Cl³⁷].

[5614]1-[(6-Carbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine:

[5615]¹H-NMR (DMSO-d₆) δ: 2.75 (2H, br s), 3.09 (4H, br), 3.63 (2H, t,J=5.9 Hz), 3.73 (2H, br s), 4.39 (2H, br s), 4.59 (2H, s), 6.17 (2H, s),7.70 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.14 (1H, d,J=8.8 Hz), 8.21 (1H, d, J=1.5 Hz), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, s).

[5616] MS (FAB) m/z: 520 [(M+H)⁺, Cl³⁵], 522 [(M+H)⁺, Cl³⁷].

[5617] Elementary analysis for C₂₂H₂₂ClN₅O₄S₂.H₂O

[5618] Calculated: C, 49.11; H, 4.50; N, 13.02.

[5619] Found: C, 48.98; H, 4.12; N, 12.83.

Example B-301-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(1-pyrrolin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[5620] In the same manner as in Example B-27, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride as a starting material.

[5621]¹H-NMR (DMSO-d₆) δ: 2.07-2.15 (2H, m), 2.94-3.16 (8H, m), 3.63(2H, t, J=7.3 Hz), 3.75 (2H, br s), 3.90 (2H, br s), 4.39 (2H, br s),4.93 (2H, s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0Hz), 8.15 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=8.8Hz), 8.50 (1H, s).

[5622] MS (FAB) m/z: 544 [(M+H)⁺, Cl³⁵], 546 [(M+H)⁺, Cl³⁷].

[5623] Elementary analysis for C₂₅H₂₆ClN₅O₃S₂.1.4HCl.CH₃OH

[5624] Calculated: C, 49.79; H, 5.05; Cl, 13.57; N, 11.17; S, 10.23.

[5625] Found: C, 49.44; H, 4.78; Cl, 13.63; N, 10.83; S, 10.15.

Example B-311-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-formyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5626] In the same manner as in Example B-7, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride and formic acid as starting materials.

[5627]¹H-NMR (DMSO-d₆) δ: 2.74-2.88 (2H, m), 3.10 (4H, br), 3.31 (2H,s), 3.66-3.86 (4H, m), 4.64-4.73 (2H, m), 7.69 (1H, dd, J=8.8, 2.0 Hz),7.82 (1H, dd, J=8.8, 2.0 Hz), 8.14 (1H, d, J=8.8 Hz), 8.15-8.22 (2H, m),8.24 (1H, d, J=8.8 Hz), 8.50 (1H, s).

[5628] MS (FAB) m/z: 505 [(M+H)⁺, Cl³⁵], 507 [(M+H)⁺, Cl³⁷].

[5629] Elementary analysis for C₂₂H₂₁ClN₄O₄S₂.⅕H₂O

[5630] Calculated: C, 51.95; H, 4.24; Cl, 6.97; N, 11.02; S, 12.61.

[5631] Found: C, 52.18; H, 4.30; Cl, 6.69; N, 10.71; S, 12.21.

Example B-321-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5632] In dichloromethane (10 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (400 mg) was suspended, followed by the addition oftriethylamine (0.22 ml) and acetic acid (0.05 ml). The resulting mixturewas stirred at room temperature for 5 minutes. To the reaction mixture,a 30% aqueous solution (0.08 ml) of formaldehyde and sodiumtriacetoxyborohydride (264 mg) were added. The resulting mixture wasstirred at room temperature for 10 minutes. The reaction mixture wasconcentrated under reduced pressure. Ethyl acetate was added to theresidue. The resulting mixture was washed with water and saturatedaqueous NaCl solution, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was dissolvedin a saturated hydrochloride solution in ethanol (1 ml), followed byconcentration under reduced pressure. The residue thus obtained wascrystallized from hexane and ethyl acetate, whereby the title compound(298 mg, 71%) was obtained.

[5633]¹H-NMR (DMSO-d₆) δ: 2.89 (3H, s), 3.10 (6H, br), 3.32-3.81 (4H,m), 4.30-4.81 (4H, m), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd,J=8.8, 2.0 Hz), 8.15 (1H, d, J=8.8 Hz), 8.20-8.28 (2H, m), 8.50 (1H, s),11.28 (1H, br s).

[5634] MS (FAB) m/z: 491 [(M+H)⁺, Cl³⁵], 493 [(M+H)⁺, Cl³⁷].

[5635] Elementary analysis for C₂₂H₂₃ClN₄O₃S₂.HCl.0.6H₂O

[5636] Calculated: C, 49.09; H, 4.72; Cl, 13.17; N, 10.41; S, 11.91.

[5637] Found: C, 48.88; H, 4.78; Cl, 13.26; N, 10.42; S, 12.03.

Example B-332-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridiniumIodide

[5638] In N,N-dimethylformamide (20 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (200 mg) was dissolved, followed by the addition of methyliodide (0.05 ml) and potassium carbonate (79.0 mg). The resultingmixture was stirred overnight at 80° C. The reaction mixture wasconcentrated under reduced pressure. Water was added to the residue andthe precipitate so formed was collected by filtration. The precipitatewas dissolved in a 1:1 mixed solution of dichloromethane and methanol.Ethyl acetate was added to the resulting solution and the precipitatethus formed was collected by filtration, whereby the title compound (144mg, 56%) was obtained.

[5639]¹H-NMR (DMSO-d₆) δ: 3.05-3.23 (12H, m), 3.77 (2H, t, J=5.9 Hz),4.40 (2H, br s), 4.79 (2H, br s), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.83(1H, dd, J=8.8, 2.0 Hz), 8.15 (1H, d, J=8.8 Hz), 8.20-8.27 (2H, m), 8.52(1H, s).

[5640] MS (FD) m/z: 505 (M⁺, Cl³⁵), 507 (M⁺, Cl³⁷)

[5641] Elementary analysis for C₂₃H₂₆ClIN₄O₃S₂.½CH₃CO₂CH₂CH₃

[5642] Calculated: C, 44.35; H, 4.47; N, 8.28.

[5643] Found: C, 44.52; H, 4.23; N, 8.01.

Example B-342-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridineN-Oxide

[5644] In acetone (10 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (400 mg) was suspended, followed by the addition of a 1Naqueous solution (0.38 ml) of sodium hydroxide and a 30% aqueoussolution (3.50 ml) of hydrogen peroxide. The resulting mixture wasstirred at room temperature for 8 days. After the reaction mixture wasconcentrated under reduced pressure, the residue was purified bychromatography through a synthetic adsorbent (“Diaion® HP-20”, tradename; water˜water:acetonitrile=2:5), whereby the title compound (84 mg,39%) was obtained.

[5645]¹H-NMR (DMSO-d₆) δ: 2.83-2.90 (1H, m), 3.10 (5H, br), 3.20-3.47(4H, m), 3.61-3.83 (3H, m), 4.28-4.50 (3H, m), 4.78-4.85 (1H, m), 7.69(1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.14 (1H, d,J=8.8 Hz), 8.19-8.27 (2H, m), 8.50 (1H, s).

[5646] MS (FD) m/z: 506 (M⁺, Cl³⁵), 508 (M⁺, Cl³⁷)

Example B-352-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineTrifluoroacetate

[5647] To trifluoroacetic acid (1 ml), a solution of1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine(303 mg) dissolved in dichloromethane (1 ml) was added, followed byconcentration under reduced pressure. The precipitate thus formed wascollected by filtration and washed with diethyl ether, whereby the titlecompound (263 mg, 83%) was obtained.

[5648]¹H-NMR (DMSO-d₆) δ: 2.39-2.70 (2H, m), 2.92-3.06 (2H, m),3.42-3.77 (4H, m), 4.25-4.50 ({fraction (7/2)}H, m), 4.97 (½H, br s),5.35-5.44 (½H, m), 6.14 (½H, br s), 7.30-7.39 (1H, m), 7.66-7.73 (2H,m), 7.77-7.82 (1H, m), 8.16 (1H, d, J=8.8 Hz), 8.21-8.28 (2H, m), 8.49(1H, s), 9.26 (2H, br s).

[5649] MS (FAB) m/z: 520 [(M+H)⁺, Cl³⁵], 522 [(M+H)⁺, Cl³⁷].

[5650] Elementary analysis for C₂₂H₂₂ClN₅O₄S₂.CF₃CO₂H.0.6H₂O

[5651] Calculated: C, 44.29; H, 3.73; Cl, 5.40; F, 9.55; N, 10.67; S,9.77.

[5652] Found: C, 44.59; H, 3.79; Cl, 5.26; F, 9.54; N, 10.28; S, 9.72.

Example B-362-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5653] In the same manner as in Example B-32, the title compound wasobtained using2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinetrifluoroacetate as a starting material.

[5654]¹H-NMR (DMSO-d₆) δ: 2.37-2.70 (2H, m), 2.91 (3H, s), 3.00-3.78(6H, m), 4.28-4.77 ({fraction (7/2)}H, m), 4.97 (½H, br s), 5.40-5.50(½H, m), 6.14 (½H, br s), 7.32-7.40 (1H, m), 7.68-7.75 (2H, m),7.77-7.83 (1H, m), 8.15 (1H, d, J=8.8 Hz), 8.21-8.28 (2H, m), 8.49 (1H,s).

[5655] MS (FAB) m/z: 534 [(M+H)⁺, Cl³⁵], 536 [(M+H)⁺, Cl³⁷].

[5656] Elementary analysis for C₂₃H₂₄ClN₅O₄S₂.HCl.2.5H₂O

[5657] Calculated: C, 44.88; H, 4.91; Cl, 11.52; N, 11.38; S, 10.42.

[5658] Found: C, 44.83; H, 4.89; Cl, 11.65; N, 11.31; S, 10.46.

Example B-371-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[5659] The crude product, which had been obtained by the reaction in thesame manner as in Example B-32 by using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (132 mg) and glyoxylic hydrate (82 mg) as startingmaterials, was suspended in tetrahydrofuran (50 ml). Triethylamine (0.22ml) and ethyl chloroformate (0.03 ml) were added to the resultingsuspension under ice cooling, followed by stirring at room temperaturefor 15 minutes. To the reaction mixture, sodium borohydride (50 mg) andwater (10 ml) were added to the reaction mixture and the resultingmixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure. The residue was diluted withdichloromethane, washed with saturated aqueous NaCl solution and driedover anhydrous sodium sulfate. The residue obtained by distilling offthe solvent under reduced pressure was purified by chromatography on asilica gel column (dichloromethane˜dichloromethane:methanol 100:3),followed by dissolution in saturated hydrochloride in ethanol (1 ml).The resulting solution was then concentrated under reduced pressure. Theconcentrate was pulverized and washed in ethyl acetate, whereby thetitle compound (52 mg, 33%) was obtained.

[5660]¹H-NMR (DMSO-d₆) δ: 3.11 (4H, br s), 3.20-3.57 (6H, m), 3.69-3.87(4H, m), 4.34-4.82 (4H, m), 5.38 (1H, br s), 7.71 (1H, dd, J=8.8, 2.0Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22 (1H, s),8.25 (1H, d, J=8.8 Hz), 8.50 (1H, s), 10.48 (1H, br s).

[5661] MS (FAB) m/z: 521 [(M+H)⁺, Cl³⁵], 523 [(M+H)⁺, Cl³⁷].

[5662] In the same manner as in Example B-32, the compounds of ExamplesB-38, B-39 and B-40 were obtained, respectively by using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride as a starting material.

Example B-381-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-2-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[5663]¹H-NMR (DMSO-d₆) δ: 3.07-3.17 (6H, m), 3.63 (2H, t, J=6.3 Hz),3.74 (2H, br s), 4.39 (2H, br s), 4.58 (2H, s), 4.61 (2H, s), 7.50-7.64(1H, m), 7.67-7.73 (2H, m), 7.82 (1H, dd, J=8.8, 1.5 Hz), 7.97 (1H, m),8.15 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=1.5 Hz), 8.25 (1H, d, J=8.8 Hz),8.50 (1H, s), 8.69 (1H, d, J=4.9 Hz).

[5664] MS (FAB) m/z: 568 [(M+H)⁺, Cl³⁵], 570 [(M+H)⁺, Cl³⁷].

[5665] Elementary analysis for C₂₇H₂₆ClN₅O₃S₂.2HCl.0.8H₂O

[5666] Calculated: C, 49.48; H, 4.55; Cl, 16.23; N, 10.68; S, 9.78.

[5667] Found: C, 49.72; H, 4.48; Cl, 16.31; N, 10.86; S, 9.53.

Example B-391-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-3-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[5668]¹H-NMR (DMSO-d₆) δ: 3.03-3.27 (6H, m), 3.40-3.81 (4H, m), 3.74(2H, br s), 4.40 (2H, br s), 4.50 (2H, s), 4.70 (2H, s), 7.70 (1H, dd,J=8.8, 2.4 Hz), 7.82 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22(1H, s), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, s), 8.73 (1H, d, J=7.8 Hz),8.93 (1H, d, J=4.4 Hz).

[5669] MS (FAB) m/z: 568 [(M+H)⁺, Cl³⁵], 570 [(M+H)⁺, Cl³⁷].

[5670] Elementary analysis for C₂₇H₂₆ClN₅O₃S₂.2.9HCl.4.5H₂O

[5671] Calculated: C, 42.96; H, 5.06; Cl, 18.32; N, 9.28.

[5672] Found: C, 42.97; H, 4.84; Cl, 18.19; N, 9.23.

Example B-401-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[5673]¹H-NMR (DMSO-d₆) δ: 3.11 (4H, br s), 3.19 (2H, br s), 3.64 (2H, brs), 3.74 (2H, br s), 4.41 (2H, br s), 4.49 (2H, s), 4.80 (2H, s), 7.69(1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd, J=8.8, 2.0 Hz), 8.15 (1H, d,J=8.8 Hz), 8.21 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=8.8 Hz), 8.41 (2H, d,J=6.3 Hz), 8.50 (1H, s), 9.04 (2H, d, J=6.3 Hz).

[5674] MS (FAB) m/z: 568 [(M+H)⁺, Cl³⁵], 570 [(M+H)⁺, Cl³⁷].

[5675] Elementary analysis for C₂₇H₂₆ClN₅O₃S₂.2.7HCl.6.0H₂O

[5676] Calculated: C, 41.86; H, 5.30; Cl, 16.93; N, 9.04; S, 8.28.

[5677] Found: C, 42.05; H, 4.98; Cl, 16.92; N, 9.37; S, 8.61.

Example B-411-[(E)-4-Chlorostyrylsulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5678] In the same manner as in Example B-1, the title compound wasobtained using1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(E)-4-chlorostyrylsulfonyl]piperazineas a starting material.

[5679]¹H-NMR (DMSO-d₆) δ: 3.04 (2H, br s), 3.23 (4H, br), 3.47 (2H, brs), 3.77 (2H, br s), 4.35-4.50 (2H, m), 7.33 (1H, d, J=15.6 Hz), 7.43(1H, d, J=15.6 Hz), 7.49 (1H, d, J=8.3 Hz), 7.79 (1H, d, J=8.3 Hz), 9.57(2H, br s).

[5680] MS (FAB) m/z: 453 [(M+H)⁺, Cl³⁵], 455 [(M+H)⁺, Cl³⁷].

[5681] Elementary analysis for C₁₉H₂₁ClN₄O₃S₂.HCl.0.3H₂O

[5682] Calculated: C, 46.12; H, 4.60; Cl, 14.33; N, 11.32; S, 12.96.

[5683] Found: C, 46.42; H, 4.66; Cl, 14.38; N, 11.02; S, 13.02.

Example B-421-[(E)-4-Chlorostyrylsulfonyl]-4-[6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5684] In the same manner as in Example B-32, the title compound wasobtained using1-[(E)-4-chlorostyrylsulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride as a starting material.

[5685]¹H-NMR (DMSO-d₆) δ: 2.92 (3H, s), 3.01-3.32 (6H, br), 3.35-3.88(4H, m), 4.29-4.84 (4H, m), 7.33 (1H, d, J=15.6 Hz), 7.49 (1H, d, J=15.6Hz), 7.49 (1H, d, J=8.3 Hz), 7.79 (1H, d, J=8.3 Hz), 11.31 (1H, br s).

[5686] MS (FAB) m/z: 467 [(M+H)⁺, Cl³⁵], 469 [(M+H)⁺, Cl³⁷].

[5687] Elementary analysis for C₂₀H₂₃ClN₄O₃S₂.HCl.0.2H₂O

[5688] Calculated: C, 47.37; H, 4.85; Cl, 13.98; N, 11.05; S, 12.65.

[5689] Found: C, 47.30; H, 4.92; Cl, 14.05; N, 11.03; S, 12.49.

Example B-43(3S)-3-[(6-Chloronaphthalen-2-yl)sulfonamido]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]pyrrolidineHydrochloride

[5690] In the same manner as in Example B-1, the title compound wasobtained using(3S)-1-[(5-tert-butoxycarbonyl-4,5,6,7-terahydrothieno[3,2-c]pyridin-2-yl)methyl]-3-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidineas a starting material.

[5691] [α]_(D)=−69.72° (25° C., c=1.00, CH₃OH).

[5692]¹H-NMR (DMSO-d₆ at 100° C.) δ: 1.88-1.89 (1H, m), 2.10-2.25 (1H,m), 3.02-3.07 (2H, m), 3.10-3.50 (6H, m), 4.02 (1H, s), 4.12 (2H, s),4.45 (2H, s), 7.12 (1H, s), 7.65 (1H, d, J=8.3 Hz), 7.91 (1H, d, J=8.3Hz), 8.10 (1H, d, J=8.3 Hz), 8.14 (1H, s), 8.16 (1H, d, J=8.3 Hz), 8.18(1H, br s), 8.48 (1H, s), 9.65 (2H, br s).

[5693] MS (FD) m/z: 461 (M⁺, Cl³⁵), 463 (M⁺, Cl³⁷)

[5694] Elementary analysis for C₂₂H₂₄ClN₃O₂S₂.2.1HCl.H₂O

[5695] Calculated: C, 47.47; H, 5.09; Cl, 19.74; N, 7.55; S, 11.52.

[5696] Found: C, 47.55; H, 5.13; Cl, 19.85; N, 7.45; S, 11.48.

Example B-44(3S)-3-[(6-Chloronaphthalen-2-yl)sulfonamido]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]pyrrolidineHydrochloride

[5697] In the same manner as in Example B-1, the title compound wasobtained using(3S)-1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-3-[(6-chloronaphthalen-2-yl)sulfonamido]pyrrolidineas a starting material.

[5698] [α]_(D)=−62.70° (25° C., c=1.00, CH₃OH).

[5699]¹H-NMR (DMSO-d₆ at 100° C.) δ: 1.82-1.90 (1H, m), 1.96-2.05 (1H,m), 3.05 (2H, t, J=6.0 Hz), 3.42-3.57 (2H, m), 3.60-3.72 (2H, m),3.84-3.90 (1H, m), 4.12 (2H, s), 4.45 (2H, s), 7.25 (1H, s), 7.64 (1H,dd, J=8.3, 1.6 Hz), 7.90 (1H, dd, J=8.3, 1.6 Hz), 7.97 (1H, d, J=5.6Hz), 8.08 (1H, d, J=8.7 Hz), 8.12 (1H, s), 8.14 (1H, d, J=8.7 Hz), 8.47(1H, s), 9.55 (2H, br s).

[5700] MS (FAB) m/z: 476 [(M+H)⁺, Cl³⁵], 478 [(M+H)⁺, Cl³⁷].

[5701] Elementary analysis for C₂₂H₂₂ClN₃O₃S₂.HCl

[5702] Calculated: C, 51.56; H, 4.52; Cl, 13.84; N, 8.20; S, 12.51.

[5703] Found: C, 51.25; H, 4.61; Cl, 13.68; N, 7.98; S, 12.36.

Example B-45(3S)-1-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]amino]pyrrolidineHydrochloride

[5704] In the same manner as in Example B-1, the title compound wasobtained using(3S)-3-[[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl]amino]-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidineas a starting material.

[5705] [α]_(D)=+34.82° (25° C., c=1.00, CH₃OH).

[5706]¹H-NMR (DMSO-d₆) δ: 1.98-2.20 (2H, m), 2.99-3.04 (2H, m),3.19-3.26 (1H, m), 3.30-3.50 (3H, m), 3.61-3.72 (1H, m), 3.52-3.60 (1H,m), 4.13 (2H, s), 4.29 (2H, s), 7.09 (1H, s), 7.71 (1H, dd, J=8.8, 2.0Hz), 7.89 (1H, dd, J=8.8, 2.0 Hz), 8.17 (1H, d, J=8.8 Hz), 8.25 (1H, d,J=2.0 Hz), 8.30 (1H, s), 8.57 (1H, s), 9.55 (2H, br s), 9.7-10.0 (1H,m).

[5707] MS (FD) m/z: 461 (M⁺, Cl³⁵), 463 (M⁺, Cl³⁷)

[5708] Elementary analysis for C₂₂H₂₄ClN₃O₂S₂.2HCl.0.2H₂O

[5709] Calculated: C, 49.06; H, 4.94; Cl, 19.75; N, 7.80; S, 11.91.

[5710] Found: C, 48.88; H, 4.97; Cl, 19.65; N, 7.67; S, 11.84.

Example B-46(3S)-3-[(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)carbonylamino]-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidineHydrochloride

[5711] In the same manner as in Example B-1, the title compound wasobtained using(3S)-3-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonylamino]1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidineas a starting material.

[5712] [α]_(D)=+33.56° (25° C., c=1.00, CH₃OH).

[5713]¹H-NMR (DMSO-d₆) δ: 1.85-1.95 (1H, m), 1.95-2.05 (1H, m), 3.04(2H, m), 3.24-3.40 (1H, m), 3.41-3.53 (3H, m), 4.04-4.24 (3H, m), 7.34(1H, s), 7.67 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=8.8 Hz), 8.03 (1H, d,J=8.8 Hz), 8.17 (1H, s), 8.22 (1H, d, J=8.8 Hz), 8.27 (1H, d, J=5.7 Hz),8.50 (1H, s), 9.59 (1H, br s), 9.71 (1H, br s).

[5714] MS (FD) m/z: 476 [(M+H)⁺, Cl³⁵], 478 [(M+H)⁺, Cl³⁷].

Example B-471-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]homopiperazineHydrochloride

[5715] In the same manner as in Example B-1, the title compound wasobtained using1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazineas a starting material.

[5716]¹H-NMR (DMSO-d₆) δ: 1.83 (2H, br s), 3.04 (2H, t, J=5.4 Hz),3.30-3.59 (6H, m), 3.60-3.88 (4H, m), 4.14 (2H, s), 7.20 (1H, br s),7.69 (1H, dd, J=8.8, 2.0 Hz), 7.84 (1H, d, J=8.8 Hz), 8.10 (1H, d, J=8.8Hz), 8.17-8.21 (2H, m), 8.50 (1H, s), 9.57 (2H, br s).

[5717] MS (FAB) m/z: 490 [(M+H)⁺, Cl³⁵], 492 [(M+H)⁺, Cl³⁷].

[5718] Elementary analysis for C₂₃H₂₅ClN₃O₃S₂.1.1HCl.0.2H₂O

[5719] Calculated: C, 51.66; H, 4.99; Cl, 13.92; N, 7.86.

[5720] Found: C, 51.46; H, 4.61; Cl, 13.55; N, 8.05.

Example B-484-[(6-Chloronaphthalen-2-yl)sulfonamido]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperidineHydrochloride

[5721] In the same manner as in Examples B-7 and B-1, the title compoundwas obtained using5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-carboxylicacid (WO94/21599) and 4-[(6-chloronaphthalen-2-yl)sulfonamido]piperidinetrifluoroacetate as starting materials.

[5722]¹H-NMR (DMSO-d₆) δ: 1.26-1.38 (2H, m), 1.58-1.65 (2H, m),2.93-3.13 (4H, m), 3.29-3.40 (3H, m), 3.90-4.05 (2H, m), 4.11 (2H, s),7.16 (1H, s), 7.68 (1H, dd, J=8.0, 2.0 Hz), 7.92 (1H, dd, J=8.8, 2.0Hz), 8.07 (1H, d, J=7.3 Hz), 8.13 (2H, d, J=8.8 Hz), 8.20 (1H, d, J=7.3Hz), 8.23 (1H, s), 8.51 (1H, s), 9.71 (2H, br s).

[5723] MS (FAB) m/z: 490 [(M+H)⁺, Cl³⁵], 492 [(M+H)⁺, Cl³⁷].

[5724] Elementary analysis for C₂₃H₂₅ClN₃O₃S₂.2.4HCl.3H₂O

[5725] Calculated: C, 43.67; H, 5.32; Cl, 19.05; N, 6.64.

[5726] Found: C, 43.85; H, 5.10; Cl, 19.07; N, 6.63.

Example B-491-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethylbenzofuran-2-yl)carbonyl]piperazine

[5727] In the same manner as in Example B-24, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-cyanobenzofuran-2-yl)carbonyl]piperazineas a starting material.

[5728]¹H-NMR (DMSO-d₆) δ: 3.11 (4H, s), 3.83 (4H, br), 5.90 (2H, br s),7.34 (1H, s), 7.64-7.75 (3H, m), 7.83 (1H, dd, J=8.8, 2.0 Hz), 7.89 (1H,s), 8.17 (1H, d, J=8.8 Hz), 8.23 (1H, d, J=1.5 Hz), 8.26 (1H, d, J=8.8Hz), 8.51 (1H, s), 9.77 (1H, s).

[5729] MS (FAB) m/z: 513 [(M+H)⁺, Cl³⁵], 515 [(M+H)⁺, Cl³⁷].

[5730] Elementary analysis for C₂₄H₂₁ClN₄O₅S.⅕H₂O

[5731] Calculated: C, 55.80; H, 4.18; Cl, 6.86; N, 10.70; S, 6.21.

[5732] Found: C, 55.65; H, 4.25; Cl, 6.81; N, 10.70; S, 6.37.

Example B-501-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-aminohydroxyiminomethylbenzothiophen-2-yl)carbonyl]piperazine

[5733] In the same manner as in Example B-24, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(5-cyanobenzothiophen-2-yl)carbonyl]piperazineas a starting material.

[5734]¹H-NMR (DMSO-d₆) δ: 3.11 (4H, s), 3.77 (4H, s), 5.87 (2H, br s),7.67 (1H, s), 7.71 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=8.8 Hz), 7.83 (1H,dd, J=8.8, 2.0 Hz), 7.94 (1H, d, J=8.8 Hz), 8.15 (1H, s), 8.17 (1H, d,J=8.8 Hz), 8.25 (1H, d, J=8.8 Hz), 8.29 (1H, d, J=8.3 Hz), 8.50 (1H, s),9.68 (1H, s).

[5735] MS (FAB) m/z: 529 [(M+H)⁺, Cl³⁵], 531 [(M+H)⁺, Cl³⁷].

[5736] Elementary analysis for C₂₄H₂₁N₄ClO₄S₂.0.3H₂O

[5737] Calculated: C, 53.94; H, 4.07; N, 10.48.

[5738] Found: C, 54.22; H, 4.17; N, 10.23.

Example B-511-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazineHydrochloride

[5739] In the same manner as in Example B-1, the title compound wasobtained using1-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazineas a starting material.

[5740]¹H-NMR (DMSO-d₆) δ: 2.89-3.29 (4H, m), 3.20-3.83 (8H, m), 4.25(2H, s), 7.10-7.25 (3H, m), 7.71 (1H, d, J=8.3 Hz), 7.81 (1H, d, J=8.3Hz), 8.17 (1H, d, J=8.8 Hz), 8.15-8.25 (2H, m), 8.49 (1H, s), 9.54 (2H,br s).

[5741] MS (FAB) m/z: 470 [(M+H)⁺, Cl³⁵], 472 [(M+H)⁺, Cl³⁷].

[5742] Elementary analysis for C₂₄H₂₄ClN₃O₃S.HCl.2.0H₂O

[5743] Calculated: C, 53.14; H, 5.39; Cl, 13.07; N, 7.75; S, 5.91.

[5744] Found: C, 53.43; H, 5.43; Cl, 13.15; N, 8.07; S, 5.55.

Example B-521-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazineHydrochloride

[5745] In the same manner as in Example B-32, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazinehydrochloride as a starting material.

[5746]¹H-NMR (DMSO-d₆) δ: 2.88 (3H, s), 2.90-3.80 (13H, m), 4.12-4.56(1H, m), 7.19 (1H, s), 7.20 (2H, d, J=6.8 Hz), 7.72 (1H, dd, J=8.8, 2.0Hz), 7.81 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.24-8.28 (2H, m),8.49 (1H, s), 10.93 (1H, br s).

[5747] MS (FAB) m/z: 484 [(M+H)⁺, Cl³⁵], 486 [(M+H)⁺, Cl³⁷].

[5748] Elementary analysis for C₂₄H₂₄ClN₃O₃S.HCl.2.3H₂O

[5749] Calculated: C, 53.44; H, 5.67; Cl, 12.62; N, 7.48; S, 5.71.

[5750] Found: C, 53.71; H, 5.81; Cl, 12.37; N, 7.26; S, 5.62.

Example B-536-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniumIodide

[5751] In the same manner as in Example B-33, the title compound wasobtained using1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazinehydrochloride as a starting material.

[5752]¹H-NMR (DMSO-d₆) δ: 2.90-3.85 (18H, m), 4.61 (2H, s), 7.19 (1H, d,J=7.8 Hz), 7.24 (1H, d, J=7.8 Hz), 7.28 (1H, s), 7.72 (1H, dd, J=8.8,1.5 Hz), 7.81 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.20-8.31 (2H,m), 8.50 (1H, s).

[5753] Elementary analysis for C₂₆H₂₉ClIN₃O₃S.H₂O

[5754] Calculated: C, 48.49; H, 4.85; N, 6.53.

[5755] Found: C, 48.66; H, 4.96; N, 6.39.

Example B-541-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5756] A reaction was effected in the same manner as in Example B-7 byusing 1-[(5-chloroindol-2-yl)sulfonyl]piperazine and lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxylate asstarting materials, whereby the title compound was obtained as brownamorphous.

[5757]¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.78-2.83 (2H, m), 2.85-2.94 (2H,m), 3.15-3.28 (4H, br), 3.67 (2H, s), 3.82-3.95 (2H, br), 4.50-4.65 (2H,br), 6.96 (1H, d, J=2.0 Hz), 7.32 (1H, dd, J=8.8, 2.0 Hz), 7.36 (1H, d,J=8.8 Hz), 7.67 (1H, s), 8.71 (1H, br).

[5758] MS (FAB) m/z: 480 [(M+H)⁺, Cl³⁵], 482 [(M+H)⁺, Cl³⁷].

[5759] Elementary analysis for C₂₀H₂₂ClN₅O₃S₂.HCl.0.5H₂O

[5760] Calculated: C, 44.64; H, 4.76; Cl, 13.18; N, 13.02; S, 11.92.

[5761] Found: C, 44.69; H, 4.72; Cl, 13.36; N, 12.76; S, 11.76.

[5762] In a similar manner to Example B-54, the compounds shown inExamples B-55 to B-60 were synthesized.

Example B-554-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine Hydrochloride

[5763]¹H-NMR (DMSO-d₆) δ: 2.50-2.63 (3H, m), 2.65-2.74 (2H, m), 2.92(3H, s), 3.00-3.14 (2H, m), 3.22-3.42 (2H, m), 3.63-3.78 (2H, m),4.23-4.29 (1H, m), 4.35-4.47 (1H, m), 4.64-4.80 (1H, m), 4.97-5.02 (½H,m), 5.45-5.51 (1H, m), 6.13-6.17 (½H, m), 7.02 (1H, br), 7.32 (1H, dd,J=8.8, 2.0 Hz), 7.47 (1H, d, J=8.3 Hz), 7.77 (1H, br), 8.07-8.16 (1H,m), 12.41 (1H, s).

[5764] MS (FAB) m/z: 537 [(M+H)⁺, Cl³⁵], 539 [(M+H)⁺, Cl³⁷].

[5765] Elementary analysis for C₂₂H₂₅ClN₆O₄S₂.HCl.1.7H₂O

[5766] Calculated: C, 43.74; H, 4.90; Cl, 11.74; N, 13.91; S, 10.62.

[5767] Found: C, 44.02; H, 5.07; Cl, 11.83; N, 13.59; S, 10.52.

Example B-564-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5768]¹H-NMR (DMSO-d₆) δ: 2.65 (3H, d, J=4.5 Hz), 2.85-3.22 (7H, m),3.22-3.38 (2H, m), 3.66 (1H, d, J=12.2 Hz), 3.55-3.68 (2H, m), 4.17-4.40(3H, m), 4.55-4.68 (1H, m), 6.99 (1H, d, J=2.0 Hz), 7.27-7.31 (2H, m),7.48 (1H, d, J=8.8 Hz), 7.77 (1H, d, J=2.0 Hz), 8.09 (1H, br s), 10.60(1H, br s), 12.41 (1H, s).

[5769] MS (FAB) m/z: 536 [(M+H)⁺, Cl³⁵], 538 [(M+H)⁺, Cl³⁷].

[5770] Elementary analysis for C₂₃H₂₆ClN₅O₄S₂.1.3HCl.0.6H₂O.1.5EtOH

[5771] Calculated: C, 47.07; H, 5.70; Cl, 12.29; N, 10.56; S, 9.67.

[5772] Found: C, 46.68; H, 5.63; Cl, 12.16; N, 10.20; S, 10.06.

Example B-571-[(5-Chlorobenzo[b]furan-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5773]¹H-NMR (DMSO-d₆) δ: 2.91 (3H, s), 3.11 (2H, br), 3.25-3.90 (4H,m), 3.76 (2H, br), 5.35-4.80 (2H, br), 4.41 (2H, br), 7.46 (1H, d, J=8.8Hz), 7.73 (1H, s), 7.84 (1H, d, J=8.8 Hz), 7.96 (1H, s), 11.48 (1H, br).

[5774] MS (FAB) m/z: 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

[5775] Elementary analysis for C₂₀H₂₁ClN₄O₄S₂.1.1HCl.0.3H₂O

[5776] Calculated: C, 45.63; H, 4.35; Cl, 14.14; N, 10.64; S, 12.18.

[5777] Found: C, 45.81; H, 4.29; Cl, 13.93; N, 10.44; S, 12.26.

Example B-581-[(6-Chlorobenzo[b]furan-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5778]¹H-NMR (DMSO-d₆) δ: 2.91 (3H, s), 3.00-3.55 (7H, m), 3.60-3.85(3H, m), 4.42 (3H, br), 4.67 (1H, br), 7.46 (1H, d, J=8.8 Hz), 7.73 (1H,s), 7.84 (1H, d, J=8.8 Hz), 7.96 (1H, s), 11.48 (1H, br).

[5779] MS (FAB) m/z: 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

[5780] Elementary analysis for C₂₀H₂₁ClN₄O₄S₂.HCl.0.17H₂O

[5781] Calculated: C, 46.15; H, 4.33; Cl, 13.62; N, 10.76; S, 12.32.

[5782] Found: C, 46.45; H, 4.41; Cl, 13.61; N, 10.58; S, 12.02.

Example B-591-[(5-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5783]¹H-NMR (DMSO-d₆) δ: 2.91 (3H, s), 2.98-3.90 (10H, m), 4.24-4.77(4H, m), 7.60 (1H, d, J=8.8 Hz), 8.05 (1H, s), 8.10-8.21 (2H, m), 11.72(1H, br s).

[5784] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

[5785] Elementary analysis for C₂₀H₂₁ClN₄O₃S₃.HCl.0.9H₂O

[5786] Calculated: C, 43.70; H, 4.36; Cl, 12.90; N, 10.19; S, 17.50.

[5787] Found: C, 43.82; H, 4.49; Cl, 13.27; N, 9.86; S, 17.32.

Example B-601-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5788]¹H-NMR (DMSO-d₆) δ: 2.91 (3H, s), 3.02-3.25 (5H, m), 3.32-3.90(6H, m), 4.33-4.55 (2H, m), 4.64-4.75 (1H, m), 7.55 (1H, dd, J=8.8, 2.0Hz), 8.06 (1H, d, J=8.8 Hz), 8.09 (1H, s), 11.42 (1H, br s)

[5789] MS (FAB) m/z: 497 [(M+H)⁺, Cl³⁵], 499 [(M+H)⁺, Cl³⁷].

[5790] Elementary analysis for C₂₀H₂₁ClN₄O₃S₃1.1HCl.1.4H₂O

[5791] Calculated: C, 42.71; H, 4.46; Cl, 13.24; N, 9.96; S, 17.11.

[5792] Found: C, 42.49; H, 4.51; Cl, 13.01; N, 9.76; S, 16.95.

Example B-612-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumIodide

[5793]1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinewas treated and purified in the same manner as in Example B-33, wherebythe title compound was obtained.

[5794] IR(KBr)cm⁻¹: 3016, 1631, 1450, 1432, 1344, 1328, 1276, 1267,1162, 1135, 998, 727, 578.

[5795]¹H-NMR (DMSO-d₆) δ: 3.10-3.23 (4H, m), 3.85 (2H, br s), 4.29 (2H,br s), 4.48 (3H, s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, d, J=8.8,2.0 Hz), 8.17 (1H, d, J=8.8 Hz), 8.23 (1H, d, J=2.0 Hz), 8.26 (1H, d,J=8.8 Hz), 8.52 (1H, s), 8.71 (1H, d, J=6.8 Hz), 8.98 (1H, d, J=6.8, 2.0Hz), 9.92 (1H, d, J=2.0 Hz)

[5796] MS (FAB) m/z: 487 [M⁺, Cl³⁵], 489 [M⁺, Cl³⁷].

Example B-624-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5797] In N,N-dimethylformamide (100 ml), lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxylate (616mg),4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazinetrifluoroacetate (1.12 g), 1-hydroxybenzotriazole monohydrate (36 mg)and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (579 mg)were dissolved and the resulting solution was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure. Dichloromethane was then added to the residue, followed bywashing with water. The organic layer was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column [Φ3.0×(1.5+8) cm, ethyl acetate:methanol=100:4], whereby a colorless foamwas obtained. The resulting foam was dissolved in 1N HCl (20 ml),followed by concentration under reduced pressure, whereby the titlecompound (845 mg) was obtained as a pale yellow foam.

[5798] IR(KBr)cm⁻¹: 3380, 1668, 1623, 1542, 1415, 1342, 1330, 1159,1135, 1078, 952, 941, 723, 578.

[5799]¹H-NMR (DMSO-d₆) δ: 2.42-2.80 (5H, m), 2.90 (3H, s), 2.95-3.80(6H, m), 4.23-4.50 ({fraction (5/2)}H, m), 4.60-4.77 (1H, m), 4.98 (½H,br s), 5.45-5.55 (1H, m), 6.15 (½H, br s), 7.71 (1H, d, J=8.8 Hz),7.78-7.82 (1H, m), 8.07-8.13 (1H, m), 8.15 (1H, d, J=8.8 Hz), 8.23 (1H,s), 8.25 (1H, d, J=8.8 Hz), 8.49 (1H, s), 11.70-12.00 (1H, m).

[5800] MS (FAB) m/z: 548 [(M+H)⁺, Cl³⁵], 550 [(M+H)⁺, Cl³⁷].

[5801] In a similar manner to Example B-62, the compounds of ExamplesB-63 to B-76 were obtained.

Example B-634-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazineHydrochloride

[5802] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[(morpholin-4-yl)carbonyl]methyl]piperazineHydrochloride

[5803]¹H-NMR (DMSO-d₆) δ: 2.35-2.83 (2H, m), 2.89 (3H, s), 2.95-3.88(18H, m), 4.31-4.45 ({fraction (3/2)}H, m), 4.67 (2H, d, J=15.1 Hz),5.03 (0.5H, br s), 5.37 (0.5H, d, J=13.7 Hz), 5.79 (½H, br s), 7.70 (1H,dd, J=8.8, 2.0 Hz), 7.81 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.23(1H, s), 8.27 (1H, d, J=8.8 Hz), 8.50 (1H, s), 11.50-11.75 (1H, m).

[5804] MS (FAB) m/z: 618 [(M+H)⁺, Cl³⁵], 620 [(M+H)⁺, Cl³⁷].

[5805] Elementary analysis for C₂₈H₃₂ClN₅O₅S₂.1.5HCl.3H₂O

[5806] Calculated: C, 46.27; H, 5.48; Cl, 12.19; N, 9.63; S, 8.82.

[5807] Found: C, 46.49; H, 5.20; Cl, 12.16; N, 9.67; S, 8.88.

Example B-64N-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]glycineEthyl Ester

[5808] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,N-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]glycineethyl ester Trifluoroacetate

[5809]¹H-NMR (DMSO-d₆) δ: 1.17-1.24 (3H, m), 2.38 (3H, s), 2.39-2.53(1H, m), 2.58-2.84 (5H, m), 3.20-3.29 (1H, m), 3.54-3.81 (4H, m),3.90-4.00 (1H, m), 4.06-4.17 (1H, m), 4.32 (1H, d, J=11.7 Hz), 4.47 (½H,d, J=13.7 Hz), 5.14 (½H, s), 5.66 (½H, d, J=13.7 Hz), 6.42 (1H, br s),7.68 (1H, d, J=8.3 Hz), 7.79 (1H, d, J=8.3 Hz), 8.12 (1H, dd, J=8.8, 3.4Hz), 8.19 (1H, s), 8.23 (1H, d, J=8.8 Hz), 8.48 (1H, s), 8.52 (½H, t,J=5.4 Hz), 8.61 (½H, t, J=5.4 Hz).

[5810] MS (FD) m/z: 619 [M⁺, Cl³⁵], 621 [M⁺, Cl³⁷].

[5811] Elementary analysis for C₂₇H₃₀ClN₅O₆S₂.0.2HCl.0.1H₂O

[5812] Calculated: C, 51.54; H, 4.87; Cl, 6.76; N, 11.13; S, 10.19.

[5813] Found: C, 51.31; H, 4.92; Cl, 6.74; N, 10.92; S, 10.01.

[5814] In the present reaction, the below-described compound whose esterbond had been hydrolyzed was obtained.N-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]glycine

[5815]¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.59-2.83 (6H, m), 3.20-3.32(1H, m), 3.52-3.77 (4H, m), 3.82-3.95 (1H, m), 4.28-4.35 (1H, m), 4.45(½H, d, J=13.7 Hz), 5.13 (½H, br s), 5.63 (½H, d, J=13.7 Hz), 6.36 (1H,br s), 7.69 (1H, d, J=8.3 Hz), 7.80 (1H, d, J=8.3 Hz), 8.12 (1H, dd,J=8.8, 3.4 Hz), 8.20 (1H, s), 8.23 (1H, d, J=8.8 Hz), 8.41 (½H, t, J=5.4Hz), 8.45-8.50 ({fraction (3/2)}H, m).

[5816] MS (FD) m/z: 592 [(M+H)⁺, Cl³⁵], 594 [(M+H)⁺, Cl³⁷].

[5817] Elementary analysis for C₂₇H₃₀ClN₅O₆S₂.H₂O

[5818] Calculated: C, 49.22; H, 4.63; Cl, 5.81; N, 11.48; S, 10.51.

[5819] Found: C, 49.11; H, 4.78; Cl, 6.02; N, 11.41; S, 10.25.

Example B-654-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-(morpholin-4-yl)carbamoyl]piperazineHydrochloride

[5820] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[N-(morpholin-4-yl)carbamoyl]piperazineTrifluoroacetate

[5821]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.58-2.84 (8H, m), 2.89 (3H, s),2.98-3.58 (3H, m), 3.40-3.80 (8H, m), 4.10-4.70 (4H, m), 7.65 (1H, dd,J=8.6, 2.4 Hz), 7.79 (1H, dd, J=8.6, 1.2 Hz), 8.09 (1H, d, J=8.6 Hz),8.14 (1H, s), 8.18 (1H, d, J=8.6 Hz), 8.42 (1H, s), 8.58 (1H, br s).

[5822] MS (FAB) m/z: 619 [(M+H)⁺, Cl³⁵], 621 [(M+H)⁺, Cl³⁷].

[5823] Elementary analysis for C₂₄H₂₆ClN₄O₅S₂.1.7HCl.1.7H₂O

[5824] Calculated: C, 45.56; H, 5.11; Cl, 13.45; N, 10.57; S, 8.93.

[5825] Found: C, 45.35; H, 5.34; Cl, 13.46; N, 12.01; S, 8.93.

Example B-66 EthylN′-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]hydrazinoacetateHydrochloride

[5826] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, ethylN′-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]hydrazinoacetateHydrochloride

[5827]¹H-NMR (DMSO-d₆) δ: 1.18-1.28 (3H, m), 2.36 (3H, s), 2.65-2.85(5H, m), 3.23-3.28 (1H, m), 3.31 (2H, s), 3.44-3.75 (4H, m), 4.08-4.24(3H, m), 4.38 (½H, d, J=13.7 Hz), 5.01 (½H, s), 5.22-5.31 (1H, m), 5.52(½H, d, J=13.7 Hz), 6.10 (½H, br s), 7.69 (1H, d, J=8.8, 2.0 Hz),7.72-7.80 (1H, m), 7.72-7.80 (3H, m), 8.47 (1H, s), 9.77-9.85 (1H, m).

[5828] MS (FAB) m/z: 635 [(M+H)⁺, Cl³⁵], 637 [(M+H)⁺, Cl³⁷].

[5829] Elementary analysis for C₂₇H₃₁ClN₆O₆S₂.1.6HCl.H₂O

[5830] Calculated: C, 45.58; H, 4.90; Cl, 12.95; N, 11.81; S, 9.01.

[5831] Found: C, 45.71; H, 5.09; Cl, 12.83; N, 11.46; S, 8.94.

Example B-674-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[N-[[(morpholin-4-yl)carbonyl]methyl]carbamoyl]piperazineHydrochloride

[5832] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[N-[[(morpholin-4-yl)carbonyl]methyl]carbamoyl]piperazineHydrochloride

[5833]¹H-NMR (DMSO-d₆) δ: 2.35-2.82 (2H, m), 2.90 (3H, s), 2.95-3.30(2H, m), 3.32-3.86 (13H, m), 4.05-4.20 (1H, m), 4.23-4.50 (2.5H, m),4.59-4.70 (1H, m), 5.15 (0.5H, s), 5.50 (0.5H, d, J=12.2 Hz), 6.30(0.5H, s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.80 (1H, d, J=8.8 Hz),8.12-8.38 (4H, m), 8.48 (1H, s), 11.45-11.75 (1H, m).

[5834] MS (FAB) m/z: 661 [(M+H)⁺, Cl³⁵], 663 [(M+H)⁺, Cl³⁷].

[5835] Elementary analysis for C₂₉H₃₃ClN₆O₆S₂.HCl.H₂O

[5836] Calculated: C, 48.67; H, 5.07; Cl, 9.91; N, 11.74; S, 8.96.

[5837] Found: C, 48.70; H, 5.03; Cl, 10.23; N, 11.55; S, 9.32.

Example B-684-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]morpholineHydrochloride

[5838] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,4-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]morpholineTrifluoroacetate

[5839] IR(KBr)cm⁻¹: 3396, 2919, 2854, 1652, 1623, 1457, 1112, 954, 723,578.

[5840]¹H-NMR (DMSO-d₆) δ: 2.62-2.79 (1H, m), 2.85-3.92 (19H, m),4.02-4.13 (½H, m), 4.30-4.49 ({fraction (3/2)}H, m), 4.58-4.80 (1H, m),5.24-5.46 (1H, m), 6.28-6.45 (1H, m), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.83(1H, d, J=8.8 Hz), 8.12-8.28 (3H, m), 8.53 (1H, s), 11.30-11.80 (1H, m).

[5841] MS (FAB) m/z: 604 [(M+H)⁺, Cl³⁵], 606 [(M+H)⁺, Cl³⁷].

Example B-694-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5842] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[ethoxycarbonyl]piperazine

[5843]¹H-NMR (CDCl₃) δ: 1.25-1.35 (3H, m), 2.43-2.94 (9H, m), 3.31 (½H,dt, J=12.7, 3.4 Hz), 3.60-3.76 (2.5H, m), 3.83 (½H, d, J=11.7 Hz), 3.89(½H, d, J=11.7 Hz), 4.19-4.30 (2H, m), 4.42-4.50 (1H, m), 4.55 (½H, 14.2Hz), 5.76 (½H, 14.2 Hz), 7.57 (1H, dd, J=8.3, 1.5 Hz), 7.77 (1H, dd,J=8.3, 1.5 Hz), 7.89-7.94 (3H, m), 8.34 (1H, s).

[5844] MS (FAB) m/z: 563 [(M+H)⁺, Cl³⁵], 565 [(M+H)⁺, Cl³⁷].

Example B-70 Methyl[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetate

[5845] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[methoxycarbonylmethyl]piperazine

[5846] IR(KBr)cm⁻¹: 2944, 2846, 2788, 1735, 1619, 1455, 1164.

[5847]¹H-NMR (CDCl₃) δ: 2.40-2.92 (10H, m), 3.04 (1H, dd, J=16.1, 8.8Hz), 3.16-3.27 (½H, m), 3.42-3.55 (½H, m), 3.60-3.72 (5H, m), 3.83-3.97(2H, m), 4.60 (½H, d, J=13.2 Hz), 5.21 (½H, br s), 5.70 (½H, d, J=13.2Hz), 6.15 (½H, br s), 7.57 (1H, dd, J=8.8, 2.0 Hz), 7.75 (1H, dd, J=8.8,2.0 Hz), 7.87-7.95 (3H, m), 8.30 (1H, s).

[5848] MS (FAB) m/z: 563 [(M+H)⁺, Cl³⁵], 565 [(M+H)⁺, Cl³⁷].

Example B-712-[[N-(tert-butoxy)amino]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineTrifluoroacetate

[5849] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[(N-tert-butoxy)carbonyl]piperazineTrifluoroacetate

[5850] IR(KBr)cm⁻¹: 2979, 1675, 1465, 1199, 1184, 1166, 1135, 721.

[5851]¹H-NMR (DMSO-d₆) δ: 1.15-1.25 (9H, m), 2.36 (3H, s), 2.37-2.49(1H, m), 2.67-2.84 (5H, m), 3.25-3.35 (1H, m), 3.59-3.78 (3H, m),4.13-4.25 (1H, m), 4.38 (1H, d, J=13.2 Hz), 5.01 (½H, br s), 5.52 (½H,d, J=13.2 Hz), 5.14 (½H, s), 6.21 (½H, br s), 7.69 (1H, dd, J=8.8, 2.0Hz), 7.76-7.74 (1H, m), 8.14 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.24 (1H,d, J=8.8 Hz), 8.47-8.53 (1H, m), 10.75-10.78 (1H, m).

[5852] MS (FAB) m/z: 606 [(M+H)⁺, Cl³⁵], 608 [(M+H)⁺, Cl³⁷].

Example B-724-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetamideHydrochloride

[5853] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[carbamoylmethyl]piperazineHydrochloride

[5854] IR(KBr)cm⁻¹: 1671, 1616, 1465, 1457, 1419, 1332, 1162, 1133,1124, 1078, 956, 701, 578.

[5855]¹H-NMR (DMSO-d₆) δ: 2.30-2.80 (4H, m), 2.90 (3H, s), 2.93-3.25(2H, m), 3.30-3.55 (1H, m), 3.62-3.88 (3H, m), 4.05-4.43 (2.5H, m),4.60-4.71 (1H, m), 5.05 (0.5H, br s), 5.34 (0.5H, d, J=13.2 Hz),5.69-5.84 (0.5H, m), 6.82 (0.5H, br s), 6.93 (0.5H, br s), 7.37-7.50(1H, m), 7.70 (1H, d, J=8.8 Hz),7.80 (1H, d, J=8.8 Hz), 8.10-8.29 (3H,m), 8.49 (1H, s).

[5856] MS (FAB) m/z: 576 [(M+H)⁺, Cl³⁵], 57.8 [(M+H)⁺, Cl³⁷].

Example B-734-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[(N-isopropyl)carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5857] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[(N-isopropyl)carbamoyl]piperazineHydrochloride

[5858] IR(KBr)cm⁻¹: 2967, 2933, 1666, 1625, 1542, 1463, 1344, 1332,1159, 1135, 954, 725, 578.

[5859]¹H-NMR (DMSO-d₆) δ: 1.00-1.10 (6H, m), 2.50-2.80 (2H, m), 2.91(3H, s), 2.93-3.50 (4H, m), 3.60-3.79 (2H, m), 3.82-3.95 (1H, m),4.18-4.30 (1H, m), 4.32-4.50 (1.5H, m), 4.60-4.77 (1H, m), 4.97 (0.5H,s), 5.03 (0.5H, d, J=13.2 Hz), 5.90 (0.5H, s), 7.70 (1H, d, J=8.8 Hz),7.79 (1H, d, J=8.8 Hz), 7.92-8.00 (1H, m), 8.22 (1H, d, J=8.8 Hz),8.18-8.28 (2H, m), 8.48 (1H, s).

[5860] MS (FAB) m/z: 576 [(M+H)⁺, Cl³⁵], 578 [(M+H)⁺, Cl³⁷].

Example B-744-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[(piperidin-1-yl)carbonyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5861] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[(piperidin-1-yl)carbonyl]methyl]piperazineHydrochloride

[5862] IR(KBr)cm⁻¹: 2931, 2854, 1623, 1455, 1334, 1159, 1135, 1124,1078, 954, 700, 578.

[5863]¹H-NMR (DMSO-d₆) δ: 1.20-1.70 (8H, m), 2.35-2.82 (2H, m), 2.90(3H, s), 2.95-3.88 (11H, m), 4.31-4.45 (1.5H, m), 4.62-4.76 (1H, m),5.03 (0.5H, br s), 5.34 (0.5H, d, J=13.2 Hz), 5.70 (0.5H, br s), 7.70(1H, d, J=8.8 Hz), 7.81 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22(1H, s), 8.27 (1H, d, J=8.8 Hz), 8.50 (1H, s).

[5864] MS (FAB) m/z: 616 [(M+H)⁺, Cl³⁵], 618 [(M+H)⁺, Cl³⁷].

Example B-754-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxybenzyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5865] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[N-(2-methoxybenzyl)]carbamoyl]piperazineHydrochloride

[5866]¹H-NMR (DMSO-d₆) δ: 2.42-3.54 (9H, m), 3.62-3.85 (5H, m),4.12-4.50 (3.5H, m), 4.60-4.77 (1H, m), 5.09 (½H, br s), 5.43-5.52 (½H,m), 6.11-6.19 (½H, m), 6.85-7.00 (2H, m), 7.16-7.29 (2H, m), 7.72 (1H,d, J=10.7 Hz), 7.80-7.86 (1H, m), 8.16 (1H, d, J=8.8 Hz), 8.22-8.28 (2H,m), 8.50 (1H, s), 8.65-8.72 (1H, m).

[5867] MS (FAB) m/z: 654 [(M+H)⁺, Cl³⁵], 656 [(M+H)⁺, Cl³⁷].

Example B-764-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5868] Starting materials: lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate,4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxyethyl)]carbamoyl]piperazine

[5869] IR(KBr)cm⁻¹: 2931, 1544, 1463, 1423, 1344, 1332, 1157, 1133,1078, 954, 943, 723, 578.

[5870]¹H-NMR (DMSO-d₆) δ: 2.42-2.82 (2H, m), 2.92 (3H, s), 2.95-3.79(13H, m), 4.21-4.80 (3.5H, m), 5.02 (½H, br s), 5.47 (½H, d, J=12.2 Hz),6.07 (½H, br s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.79 (1H, d, J=8.8 Hz),8.13 (1H, d, J=8.8 Hz), 8.17-8.32 (3H, m), 8.48 (1H, s), 11.09-11.40(1H, m).

[5871] MS (FAB) m/z: 592 [(M+H)⁺, Cl³⁵], 594 [(M+H)⁺, Cl³⁷].

Example B-774-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicAcid

[5872] In tetrahydrofuran (10 ml),4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine(2.08 g) was dissolved, followed by the addition of ethanol (20 ml) anda 1N aqueous solution (3.70 ml) of sodium hydroxide. The resultingmixture was stirred at room temperature for 1 hour. After concentrationof the reaction mixture under reduced pressure, the residue was addedwith water (20 ml). The precipitate thus formed was collected byfiltration, whereby the title compound (1.39 g) was obtained as a paleyellow foam.

[5873] IR(KBr)cm⁻¹: 1731, 1625, 1461, 1346, 1332, 1315, 1159, 1135,1078, 954, 943, 723, 580.

[5874]¹H-NMR (DMSO-d₆) δ: 2.32-3.86 (11H, m), 4.27 (1H, d, J=11.7 Hz),4.35-4.48 ({fraction (3/2)}H, m), 4.59-4.78 (1H, m), 5.21 (½H, m),5.38-5.52 (½H, m), 6.34-6.47 (½H, m), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.83(1H, d, J=8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.23 (1H, s), 8.27 (1H, d,J=8.8 Hz), 8.53 (1H, s), 11.60-11.90 (1H, m).

[5875] Elementary analysis for C₂₃H₂₃ClN₄O₅S₂.1.3HCl.1.5H₂O

[5876] Calculated: C, 45.33; H, 4.51; Cl, 13.38; N, 9.19; S, 10.52.

[5877] Found: C, 45.69; H, 4.55; Cl, 13.29; N, 9.21; S, 10.21.

Example B-78N′-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]hydrazinoaceticAcid

[5878] In the same manner as in the Example B-77, the title compound wasobtained using ethylN′-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]hydrazinoacetatehydrochloride as a starting material.

[5879] MS (FAB) m/z: 607 [(M+H)⁺, Cl³⁵], 609 [(M+H)⁺, Cl³⁷].

[5880]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.41 (3H, s), 2.65-3.30 (6H, m),3.37-3.77 (8H, m), 4.16 (1H, d, J=12.7 Hz), 7.64 (1H, dd, J=8.7, 2.4Hz), 7.78 (1H, dd, J=8.7, 1.6 Hz), 8.07 (1H, d, J=8.7 Hz), 8.11 (1H, d,J=1.6 Hz), 8.16 (1H, d, J=8.7 Hz), 8.42 (1H, s).

[5881] Elementary analysis for C₂₅H₂₇ClN₅O₅S₂.2H₂O

[5882] Calculated: C, 46.69; H, 4.86; N, 13.07; S, 9.97.

[5883] Found: C, 46.87; H, 4.86; N, 12.82; S, 9.62.

Example B-794-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[N-(tetrahydropyran-2-yloxy)]carbamoyl]piperazine

[5884] In N,N-dimethylformamide (20 ml),4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylicacid (141 mg), 2-tetrahydropyranyloxyamine (180 mg),1-hydroxybenzotriazole monohydrate (11 mg),1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg) andpotassium carbonate (129 mg) were dissolved, followed by stirringovernight at room temperature. The reaction mixture was concentratedunder reduced pressure. Dichloromethane was added to the residue,followed by washing with water. The organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (Φ 0.7×25.0 cm, dichloromethane:methanol=100:3), whereby thetitle compound (308 mg) was obtained as a colorless foam.

[5885]¹H-NMR (CDCl₃) δ: 1.50-1.89 (6H, m), 2.45-2.55 (3H, m), 2.72-3.00(6H, m), 3.57-3.97 (5H, m), 4.28 (0.5H, d, J=12.2 Hz), 4.35 (0.5H, d,J=12.2 Hz), 4.52-4.61 (0.5H, m), 4.92 (0.5H, s), 502 (0.5H, br, s),5.06-5.10 (0.5H, m), 5.55-5.65 (0.5H, m), 5.88 (0.5H, br s), 6.21 (0.5H,br s), 7.51-7.58 (1H, m), 7.77-7.93 (4H, m), 8.35 (1H, s), 9.61 (0.5H,br s), 10.10 (1H, br s).

[5886] MS (FAB) m/z: 634 [(M+H)⁺, Cl³⁵], 636 [(M+H)⁺, Cl³⁷].

Example B-804-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carbohydroxamicAcid

[5887] In methanol (10 ml),4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[N-(tetrahydropyran-2-yloxy)]carbamoyl]piperazine(297 mg) was dissolved, followed by the addition of 1N hydrochloric acid(10 ml). The resulting mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by “HP-20” (Φ 1.7×20.0 cm, acetonitrile:water=1:5),whereby the title compound (65 mg) was obtained as a pale yellow foam.

[5888]¹H-NMR (CDCl₃) δ: 2.32-2.73 (2H, m), 2.91 (3H, s), 2.97-3.30 (3H,m), 3.35-3.50 (1H, m), 3.63-3.76 (2H, m), 4.22-4.48 (2.5H, m), 4.61-4.75(1H, m), 4.99 (0.5H, s), 5.47 (0.5H, d, J=12.2 Hz), 6.24 (0.5H, s), 7.70(1H, d, J=8.8 Hz), 7.75-7.85 (1H, m), 8.15 (1H, d, J=8.8 Hz), 8.23 (1H,s), 8.25 (1H, d, J=8.8 Hz), 8.48 (1H, s), 10.26 (1H, br s), 10.97 (1H,br s).

[5889] MS (FAB) m/z: 550 [(M+H)⁺, Cl³⁵], 552 [(M+H)⁺, Cl³⁷].

Example B-814-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-hydroxybenzyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5890] In dichloromethane (10 ml),4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxybenzyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (195 mg) was dissolved, followed by the dropwise additionof a boron tribromide—dichloromethane solution (1.0M, 2.08 ml) at −78°C. The reaction mixture was heated to room temperature and stirredovernight. To the reaction mixture, methanol (2 ml), sodium carbonate(200 mg) and water (3 ml) were added to extract the organic layer,followed by drying over anhydrous sodium sulfate. The solvent was thendistilled off under reduced pressure. The solid thus precipitated wascollected by filtration while being washed with 1N hydrochloric acid,whereby the title compound (50 mg, 24%) was obtained as a pale yellowsolid.

[5891]¹H-NMR (DMSO-d₆) δ: 2.36-2.87 (9H, m), 3.11-3.28 (1H, m),3.59-3.80 (3H, m), 4.12-4.45 (3.5H, m), 4.48-4.57 (½H, m), 5.08 (½H, brs), 6.19 (½H, br s), 6.63-6.81 (2H, m), 6.98-7.15 (2H, m), 7.70 (1H, dd,J=8.3, 1.5 Hz), 7.78-7.84 (1H, m), 8.13 (1H, d, J=8.8 Hz), 8.20-8.28(2H, m), 8.49 (1H, s), 8.50-8.62 (1H, m), 9.45 (½H, s), 9.50 (½H, s).

[5892] MS (FAB) m/z: 640 [(M+H)⁺, Cl³⁵], 642 [(M+H)⁺, Cl³⁷].

Example B-822-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridineHydrochloride

[5893] To a solution of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine(58.1 mg) in tetrahydrofuran (3.2 ml), n-butyl lithium (a 1.59N hexanesolution, 320 μl) was added at −78° C., followed by stirring for 1 hourand then at 0° C. for 30 minutes. The reaction mixture was cooled to−78° C. and a carbon dioxide gas was introduced thereinto for 1 hour.After the reaction mixture was heated to room temperature over 30minutes, it was concentrated. To a solution of the resulting residue inN,N-dimethylformamide (6.0 ml),1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (177 mg,510 μmol) was dissolved, followed by the addition of1-(dimethylaminopropyl)-3-ethylcarbodiimide (98.0 mg, 511 mmol) and1-hydroxybenzotriazole (69.0 mg, 511 μmol) at room temperature and then,diisopropylethylamine (185 μl, 1.06 mmol) at 0° C. After stirringovernight at room temperature, the reaction mixture was added withmethylene chloride (20 ml) and a saturated aqueous solution (50 ml) ofsodium bicarbonate, whereby the organic layer was separated. Theresulting organic layer was extracted with methylene chloride (2×10 ml).The organic layers were combined, washed with water (50 ml), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified twice by preparative thin-layerchromatography on a silica gel (methylenechloride:acetone:ethanol=10:5:1). The white solid thus obtained wasdissolved in a 1N ethanol hydrochloride solution and the resultingsolution was concentrated. After the addition of water, the mixture wasconcentrated again, whereby the title compound (74.7 mg) was obtained asa white solid.

[5894] IR(KBr)cm⁻¹: 3396, 2918, 2850, 2538, 1620, 1456, 1432, 1344,1329, 1282, 1161, 955, 941, 729.

[5895]¹H-NMR (DMSO-d₆) δ: 2.68 (1H, br d, J=15.1 Hz), 2.78-2.92 (1H,br), 2.85 (3H, s), 3.04 (4H, br s), 3.26 (1H, br s), 3.52 (1H, br s),3.72 (4H, br s), 4.20 (1H, br d, J=15.1 Hz), 4.43 (1H, br d, J=15.1 Hz),6.92 (1H, s), 7.71 (1H, dd, J=2.0, 8.8 Hz), 7.80 (1H, d, J=8.8 Hz), 8.15(1H, d, J=8.8 Hz), 8.23 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.48 (1H, s),11.64 (1H, br s).

[5896] MS (FAB) m/z: 474 [(M+H)⁺].

[5897] Elementary analysis for C₂₃H₂₄ClN₃O₄S.1.1HCl.1.7H₂O

[5898] Calculated: C, 50.72; H, 5.27; N, 7.71; Cl, 13.67; S, 5.89.

[5899] Found: C, 50.58; H, 5.39; N, 7.69; Cl, 13.94; S, 5.85.

Example B-832-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5,6,7,8-tetrahydro-1,6-naphthyridineHydrochloride

[5900] To6-(t-butoxycarbonyl)-2-[[4-(chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5,6,7,8-tetrahydro1,6-naphthyridine (1.28 g, 2.24 mmol), a saturated ethanol hydrochloridesolution (50 ml) was added at room temperature. The resulting mixturewas stirred for 20 minutes, followed by concentration, whereby the titlecompound (1.26 g) was obtained as a white solid.

[5901] IR(KBr)cm⁻¹: 3396, 2924, 2615, 2544, 1957, 1655, 1610, 1473,1454, 1425, 1448, 1336, 1286, 1157, 941, 731, 580.

[5902]¹H-NMR (DMSO-d₆) δ: 3.02 (2H, br t, J=5.3 Hz), 3.05 (2H, t, J=6.4Hz), 3.42-3.49 (2H, brm), 3.52 (2H, br t, J=5.3 Hz), 3.75 (2H, br t,J=5.3 Hz), 4.33 (2H, br t, J=5.3 Hz), 7.56 (1H, br d, J=8.3 Hz), 7.89(1H, d, J=8.3 Hz), 7.89 (1H, dd, J=1.5, 8.8 Hz), 7.98 (1H, dd, J=2.0,8.8 Hz), 8.34 (1H, d, J=8.8 Hz), 8.43 (1H, s), 8.44 (1H, d, J=8.8 Hz),8.67 (1H, br s), 9.87 (2H, br s).

[5903] MS (FAB) m/z: 471 [(M+H)⁺, Cl³⁵].

[5904] Elementary analysis for C₂₃H₂₃ClN₄O₃S.1.9HCl.0.9H₂O

[5905] Calculated: C, 49.64; H, 4.84; Cl, 10.07; N, 18.48; S, 5.76.

[5906] Found: C, 49.64; H, 4.96; Cl, 10.01; N, 18.73; S, 5.93.

Example B-842-[[4-(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridineHydrochloride

[5907] To a solution of2-[[4-(chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5,6,7,8-tetrahydro1,6-naphthyridine (174 mg) in methylene chloride (3.5 ml), triethylamine(95.6 μl), acetic acid (58.9 μl), formaldehyde (a 37% aqueous solution,42.0 μl) and sodium triacetoxyborohydride (110 mg) were added at roomtemperature, followed by stirring for 15 minutes. To the reactionmixture, a saturated aqueous solution (10 ml) of sodium bicarbonate andmethylene chloride (10 ml) were added to separate the water layer. Theresulting water layer was extracted with methylene chloride (10 ml). Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative thin-layer chromatography on a silica gel (methylenechloride:methanol=15:1). The white solid thus obtained was dissolved ina 1N aqueous hydrochloride in ethanol, followed by concentration,whereby the title compound (170 mg) was obtained as a white solid.

[5908] IR(KBr)cm⁻¹: 3359, 2918, 2544, 1655, 1641, 1475, 1431, 1342,1331, 1284, 1155, 953, 941, 727, 579.

[5909]¹H-NMR (DMSO-d₆) δ: 3.04 (3H, d, J=3.9 Hz), 3.17 (2H, br s), 3.26(2H, br s), 3.38-3.65 (2H, m), 3.68 (2H, br s), 3.39 (2H, br s),4.40-4.70 (2H, m), 4.57 (2H, br s), 7.57 (1H, d, J=7.8 Hz), 7.84-7.92(2H, m), 7.98 (1H, d, J=8.8 Hz), 8.33 (1H, d, J=8.3 Hz), 8.42 (1H, s),8.43 (1H, d, J=8.8 Hz), 8.67 (1H, s), 11.86 (1H, br s).

[5910] MS (FAB) m/z: 485 [(M+H)⁺, Cl³⁵].

Example B-852-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridineHydrochloride

[5911] A saturated solution of hydrochloride in ethanol (25 ml) wasadded to1,5-bis(t-butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(300 mg) at room temperature, followed by stirring for 1 hour. Thereaction mixture was concentrated and water was added to theconcentrate. The resulting mixture was concentrated under reducedpressure. To the residue, a saturated solution of hydrochloride inmethanol (25 ml) was added at room temperature, followed by stirring for1 hour. After concentration of the reaction mixture, water was added andthe resulting mixture was concentrated under reduced pressure, wherebythe title compound (200 mg) was obtained as a white solid.

[5912] IR(KBr)cm⁻¹: 3290, 2918, 2762, 2559, 1614, 1483, 1454, 1381,1340, 1323, 1244, 1155, 1147, 1136, 978, 955, 727, 575.

[5913]¹H-NMR (DMSO-d₆) δ: 2.77 (2H, br t, J=5.9 Hz), 3.03 (4H, t, J=5.3Hz), 3.30 (2H, br t, J=5.9 Hz), 3.73 (4H, br t, J=5.3 Hz), 3.99 (2H, brs), 6.32 (1H, d, J=2.0 Hz), 7.73 (1H, dd, J=2.0, 8.8 Hz), 7.83 (1H, dd,J=2.0, 8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=2.0 Hz), 8.28(1H, d, J=8.8 Hz), 8.50 (1H, br s), 9.07 (2H, br), 11.38 (1H, br).

[5914] MS (FAB) m/z: 459 [(M+H)⁺, Cl³⁵].

[5915] Elementary analysis for C₂₂H₂₃ClN₄O₃S.1.1HCl.0.3H₂O

[5916] Calculated: C, 52.38; H, 4.94; N, 11.11; Cl, 14.76; S, 6.36.

[5917] Found: C, 52.48; H, 4.92; N, 11.07; Cl, 14.48; S, 6.65.

Example B-862-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridineHydrochloride

[5918] In methylene chloride (4.5 ml),2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridinehydrochloride (200 mg) was suspended, followed by the addition oftriethylamine (125 μl), acetic acid (77.0 μl), formaldehyde (a 37%aqueous solution, 56.1 μl) and sodium triacetoxyborohydride (139 mg) atroom temperature. The resulting mixture was stirred for 15 minutes. Tothe reaction mixture, a saturated aqueous solution (20 ml) of sodiumbicarbonate and methylene chloride (10 ml) were added to separate thewater layer. The resulting water layer was extracted with methylenechloride (2×10 ml). The organic layers were combined, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by chromatography on a silica gelcolumn (25 g of silica gel, methylene chloride:methanol=10:1→7:1). Theresulting solid was dissolved in a 1N aqueous hydrochloride in ethanol.After concentration of the resulting solution, water was added to theconcentrate and the mixture was concentrated again, whereby the titlecompound (133 mg) was obtained as a white solid.

[5919] IR(KBr)cm⁻¹: 3213, 2918, 2650, 2530, 1604, 1585, 1508, 1491,1456, 1342, 1331, 1157, 727, 579.

[5920]¹H-NMR (DMSO-d₆) δ: 2.72-2.86 (1H, m), 2.83 (3H, d, J=4.9 Hz),2.87-2.99 (1H, m), 3.03 (4H, br t, J=4.4 Hz), 3.19-3.31 (1H, m),3.46-3.64 (1H, m), 3.74 (4H, br t, J=4.4 Hz), 3.97 (1H, dd, J=7.8, 14.2Hz), 4.20 (1H, br d, J=14.2 Hz), 6.32 (1H, d, J=2.4 Hz), 7.72 (1H, dd,J=2.4, 8.8 Hz), 7.82 (1H, dd, J=2.0, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz),8.25 (1H, d, J=2.0 Hz), 8.27 (1H, d, J=8.8 Hz), 8.51 (1H, br s), 10.84(1H, br s), 11.42 (1H, br s).

[5921] MS (FAB) m/z: 473 [(M+H)⁺, Cl³⁵].

[5922] Elementary analysis for C₂₃H₂₅ClN₄O₃S.1.3HCl.0.7H₂O

[5923] Calculated: C, 51.83; H, 5.24; N, 10.51; Cl, 15.30; S, 6.02.

[5924] Found: C, 51.83; H, 5.37; N, 10.30; Cl, 15.35; S, 6.09.

Example B-872-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridineHydrochloride

[5925] In methylene chloride (3.0 ml),2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridinehydrochloride (149 mg) was suspended, followed by the addition ofmethanol (0.6 ml), triethylamine (82.5 μl), acetic acid (51.0 μl, 891mmol), acetaldehyde (19.5 μl) and sodium triacetoxyborohydride (74.0 mg)at room temperature. The resulting mixture was stirred for 15 minutes.To the reaction mixture, a saturated aqueous solution (30 ml) of sodiumbicarbonate and methylene chloride (15 ml) were added to separate thewater layer. The resulting water layer was extracted with methylenechloride (2×10 ml). The organic layers were combined, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by chromatography on a silica gelcolumn (30 g of silica gel, methylene chloride:methanol=10:1). Theresulting white solid was dissolved in a 1N aqueous hydrochloride inethanol (10 ml). After concentration of the resulting solution, water(30 ml) was added to the concentrate and the mixture was concentratedagain, whereby the title compound (81.7 mg) was obtained as a whitesolid.

[5926] IR(KBr)cm⁻¹: 3386, 3226, 2918, 2586, 1603, 1585, 1491, 1454,1427, 1344, 1331, 1163, 1136, 1078, 933, 727, 579.

[5927]¹H-NMR (DMSO-d₆) δ: 1.26 (3H, t, J=7.3 Hz), 2.72-2.82 (1H, m),2.86-3.00 (1H, m), 3.02 (4H, br s), 3.12-3.64 (6H, m), 3.73 (4H, br s),3.96 (1H, dd, J=7.8, 14.1 Hz), 4.22 (1H, br d, J=14.1 Hz), 6.31 (1H, d,J=2.4 Hz), 7.71 (1H, br d, J=8.8 Hz), 7.81 (1H, br d, J=8.8 Hz), 8.16(1H, d, J=8.8 Hz), 8.23 (1H, br s), 8.26 (1H, d, J=8.8 Hz), 8.50 (1H, brs), 10.39 (1H, br s), 11.40 (1H, br s)

[5928] MS (FAB) m/z: 486 [(M+H)⁺, Cl³⁵].

[5929] Elementary analysis for C₂₄H₂₇ClN₄O₃S.1.2HCl.2.0H₂O

[5930] Calculated: C, 50.86; H, 5.73; N, 9.88; Cl, 13.76; S, 5.66.

[5931] Found: C, 51.11; H, 5.71; N, 9.58; Cl, 13.60; S, 5.66.

Example B-885-(t-Butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

[5932] In methylene chloride (15 ml),2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridinehydrochloride (780 mg) was suspended, followed by the addition of asaturated aqueous solution (15 ml) of sodium bicarbonate and di-t-butyldicarbonate (506 ml) at room temperature. The resulting mixture wasstirred for 1 hour. To the reaction mixture, water (30 ml) and methylenechloride (30 ml) were added to separate the water layer. The resultingwater layer was extracted with methylene chloride (2×20 ml). The organiclayers were combined, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue thus obtained waspurified by chromatography on a silica gel column (75 g of silica gel,methylene chloride:acetone=8:1→2:1). The resxulting white solid wasdissolved in a 1N aqueous hydrochloride in ethanol. After concentrationof the resulting solution, water was added to the concentrate and themixture was concentrated again, whereby the title compound (641 mg) wasobtained as a white solid.

[5933]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.61 (2H, br s), 3.12 (4H, br t,J=4.9 Hz), 3.66 (2H, br s), 3.90 (4H, br t, J=4.9 Hz), 4.36 (2H, br s),6.19 (1H, d, J=2.0 Hz), 7.57 (1H, dd, J=1.7, 9.0 Hz), 7.76 (1H, br d,J=8.8 Hz), 7.86-7.97 (3H, m), 8.29 (1H, br s), 9.24 (1H, br s).

Example B-895-(t-Butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine

[5934] To a solution of5-(t-butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(33.0 mg) in N,N-dimethylformamide (15 ml), sodium hydride (60% in oil,3.5 mg) was added at 0° C. After stirring for 10 minutes, methyl iodide(4.5 μl) was added and the resulting mixture was stirred at 0° C. for 1hour. To the reaction mixture, a saturated aqueous solution (10 ml) ofammonium chloride, methylene chloride (20 ml) and water (30 ml) wereadded to separate the organic layer. The resulting water layer wasextracted with methylene chloride (10 ml). The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by preparative thin-layerchromatography on a silica gel (methylene chloride:acetone=9:1), wherebythe title compound (32.3 mg) was obtained as a colorless, transparentviscous substance.

[5935]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.58 (2H, br s), 3.12 (4H, br t,J=4.5 Hz), 3.50 (3H, s), 3.68 (2H, br s), 3.84 (4H, br t, J=4.5 Hz),4.32 (2H, br s), 6.02 (1H, s), 7.58 (1H, dd, J=2.0, 8.8 Hz), 7.77 (1H,dd, J=1.7, 8.5 Hz), 7.88-7.97 (3H, m), 8.32 (1H, br s).

Example B-902-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridineHydrochloride

[5936] To5-(t-butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine(280 mg), a saturated solution hydrochloride in ethanol (25 ml) wasadded at room temperature, followed by stirring for 1 hour. The reactionmixture was then concentrated. Water (10 ml) was added to theconcentrate, followed by concentration under reduced pressure, wherebythe title compound (210 mg) was obtained as a white solid.

[5937] IR(KBr)cm⁻¹: 3381, 2918, 2748, 1622, 1583, 1495, 1454, 1342,1331, 1248, 1163, 1136, 953, 935, 879, 726, 579, 476.

[5938]¹H-NMR (DMSO-d₆) δ: 2.81 (2H, br t, J=5.6 Hz), 3.05 (4H, br s),3.35 (2H, br t, J=5.6 Hz), 3.42 (3H, s), 3.69 (4H, br s), 3.97 (2H, brs), 6.18 (1H, s), 7.73 (1H, dd, J=2.0, 8.8 Hz), 7.83 (1H, dd, J=2.0, 8.8Hz), 8.18 (1H, d, J=8.8 Hz), 8.27 (1H, br s), 8.28 (1H, d, J=8.8 Hz),8.50 (1H, br s), 9.34 (1H, br d, J=27.4 Hz).

[5939] MS (FAB) m/z: 473 [(M+H)⁺, Cl³⁵].

[5940] Elementary analysis for C₂₃H₂₅ClN₄O₃S.1.4HCl.1.2H₂O

[5941] Calculated: C, 50.63; H, 5.32; N, 10.27; Cl, 15.59; S, 5.88.

[5942] Found: C, 50.71; H, 5.53; N, 10.14; Cl, 15.53; S, 5.90.

Example B-912-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1,5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridineHydrochloride

[5943] In methylene chloride (10 ml),2-[[4-(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridinehydrochloride (170 mg) was suspended, followed by the addition ofmethanol (10 ml), triethylamine (100 μl), acetic acid (62.0 μl),formaldehyde (a 37% aqueous solution, 46.5 μl) and sodiumtriacetoxyborohydride (115 mg) at room temperature. The resultingmixture was stirred for 30 minutes. To the reaction mixture, a saturatedaqueous solution (50 ml) of sodium bicarbonate and methylene chloride(30 ml) were added to separate the water layer. The water layer thusobtained was extracted with methylene chloride (2×10 ml). The organiclayers were combined, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (30 g of silica gel, methylenechloride:methanol=10:1→7:1). The resulting white solid was dissolved ina 1N aqueous hydrochloride in ethanol. After the concentration of theresulting solution, water was added to the concentrate and the resultingmixture was concentrated again, whereby the title compound (162 mg) wasobtained as a white solid.

[5944] IR(KBr)cm⁻¹: 3396, 2924, 2663, 2586, 1622, 1581, 1456, 1342,1329, 1248, 1163, 1136, 955, 937, 727, 579.

[5945]¹H-NMR (DMSO-d₆) δ: 2.77-3.00 (5H, m), 3.06 (4H, br s), 3.23-3.37(1H, m), 3.43 (3H, s), 3.55-3.65 (1H, m), 3.69 (4H, br s), 3.90-4.03(1H, m), 3.93 (3H, s), 4.19 (1H, br d, J=11.7 Hz), 6.18 (1H, s), 7.74(1H, dd, J=2.0, 8.8 Hz), 7.83 (1H, dd, J=2.0, 8.8 Hz), 8.18 (1H, d,J=8.8 Hz), 8.27 (1H, br s), 8.28 (1H, d, J=8.8 Hz), 8.51 (1H, br s),11.00 (1H, br s).

[5946] MS (FAB) m/z: 487 [(M+H)⁺, Cl³⁵].

[5947] Elementary analysis for C₂₄H₂₇ClN₄O₃S.1.4HCl.1.4H₂O

[5948] Calculated: C, 51.18; H, 5.58; N, 9.95; Cl, 15.11; S, 5.69.

[5949] Found: C, 51.09; H, 5.83; N, 9.78; Cl, 15.37; S, 5.79.

Example B-922-(N-Methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine

[5950] In N,N-dimethylformamide (5 ml) was dissolved3-(N-methylcarbamoyl)-1-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine(218 mg), followed by the addition of lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c-]pyridine-2-carboxylate (188mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240mg) and 1-hyroxybenzotriazole (68 mg). The resulting mixture was stirredat room temperature for 30 minutes. The reaction mixture was dilutedwith methylene chloride, washed with water (twice) and then with asaturated aqueous solution of sodium bicarbonate. After drying overanhydrous sodium sulfate, the solvent was distilled off under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (methanol:methylene chloride=3:97→5:95→7:93), whereby the titlecompound (90 mg) was obtained.

[5951] MS (FAB) m/z: 616 (M+H)⁺.

Example B-934-[(6-Ethynylbenzo[b]thien-2-yl)sulfonyl]-2-[N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5952] In a mixed solvent of tetrahydrofuran (0.5 ml) and methanol (0.5ml) was dissolved2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine(90 mg), followed by the addition of a 1N aqueous solution (0.3 ml) ofsodium hydroxide. The resulting mixture was stirred at room temperaturefor 2 hours. The reaction mixture was made weakly acidic with asaturated aqueous solution of ammonium chloride and then made weaklyalkaline with a saturated aqueous solution of sodium bicarbonate. Thesolution was extracted (four times) with methylene chloride. The organiclayers were combined, dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby preparative thin-layer chromatography (methanol:methylenechloride=1:9). Similar reaction and post treatment were repeated threetimes and the purified products were combined, followed by purificationthrough Sephadex LH-20 (elution with methanol). The amorphous substancethus obtained was dissolved in methylene chloride. Hexane was addeddropwise to the resulting solution, whereby the title compound (82 mg)was obtained as a light gray solid.

[5953]¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.80-2.90 (10H, m), 3.15-3.18 (1H,m), 3.22 (1H, s), 3.53-3.62 (1H, m), 3.67 (1H, s), 4.49 (1H, d, J=12.2Hz), 4.65, 5.74 (total 1H, each d, J=13.7 Hz), 5.26, 6.18 (total 1H,each s), 6.45, 6.49 (total 1H, each s), 7.54 (1H, d, J=8.3 Hz), 7.80(1H, s), 7.82 (1H, d, J=8.3 Hz), 7.97 (1H, s).

[5954] MS (FAB) m/z: 544 (M+H)⁺.

Example B-941-[(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[5955] In methylene chloride (5 ml) was dissolved1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine(930 mg), followed by the addition of trifluoroacetic acid (2 ml). Theresulting mixture was stirred at room temperature for 30 minutes. Asaturated aqueous solution of sodium bicarbonate was added and theresulting mixture was extracted with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate and distilled underreduced pressure to remove the solvent. The residue was dissolved inN,N-dimethylformamide (10 ml), followed by the addition of lithium6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(695 mg), 1-ethyl-3-(3-dimethylainopropyl)carbodiimide hydrochloride(506 mg) and 1-hydroxybenzotriazole (119 mg). The resulting mixture wasstirred overnight at room temperature. A saturated aqueous solution ofsodium bicarbonate was added and the resulting mixtures was extractedwith methylene chloride. The extract was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column(hexane:ethyl acetate=1:1), whereby the title compound (585 mg) wasobtained as an orange foam.

[5956]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.58-3.96 (19H, m), 4.60-6.02 (4H,m), 6.98 (1H, s), 7.27 (1H, d, J=9.0 Hz), 7.38 (1H, d, J=9.0 Hz), 7.64(H, s), 10.39 (1H, s).

Example B-954-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[5957] In methylene chloride (5 ml) was dissolved1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine(585 mg), followed by the addition of trifluoroacetic acid (2 ml). Theresulting mixture was stirred at room temperature for 30 minutes. Asaturated aqueous solution of sodium bicarbonate was added and theresulting mixture was extracted with methylene chloride (to whichN,N-dimethylformamide was added in a small amount). The organic layerwas dried over anhydrous sodium sulfate and distilled under reducedpressure to remove the solvent. To the residue was added a 1N aqueoushydrochloride in ethanol (1 ml) and the solvent was distilled off underreduced pressure, whereby the hydrochloride (585 mg, containing twomolecules of N,N-dimethylformamide). A 100 mg portion of the resultinghydrochloride was added to methylene chloride (3 ml), followed by theaddition of triethylamine (0.5 ml) and methanesulfonyl chloride (20 mg).The resulting mixture was stirred at room temperature for 2 hours. Asaturated aqueous solution of sodium bicarbonate was added to thereaction mixture. The resulting mixture was extracted with methylenechloride. The extract was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by preparative thin-layer chromatography (methylenechloride:methanol=9:1). The solid thus obtained was dissolved inmethylene chloride, followed by the addition of ether forcrystallization, whereby the title compound (34.2 mg) was obtained as awhite solid.

[5958]¹H-NMR (DMSO-d₆) δ: 2.33-3.57 (20H, m), 3.72-3.79 (2H, m), 4.38,5.39 (total 1H, each d, J=12.2, 13.7 Hz), 4.55 (2H, s), 5.06, 5.82(total 1H, each br s), 7.02 (1H, s), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H,d, J=8.8 Hz), 7.76 (1H, s), 12.41 (1H, s)

[5959] MS (FAB) m/z: 671 (M+H)⁺.

Example B-964-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineTrifluoroacetate

[5960] In N,N-dimethylformamide (50 ml) were dissolved6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylicacid (530 mg),4-[(5-chloronaphthalen-2-yl)sulfonyl]-2-[(N-methyl)carbamoyl]piperazinehydrochloride (527 mg) and 1-hydroxybenzotriazole monohydrate (200 mg)and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (324 mg),followed by the addition of triethylamine (0.18 ml). The resultingmixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure. Methylene chloride was added tothe residue and the resulting mixture was washed with water andsaturated aqueous NaCl solution, each once. The organic layer was driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was purified by chromatography on asilica gel column (methylene chloride:methanol=100:1), whereby paleyellow foam (577 mg) was obtained. The resulting foam was dissolved inmethylene chloride (3 ml), followed by the addition of trifluoroaceticacid (6 ml). The resulting mixture was concentrated under reducedpressure. The precipitate so formed was collected by filtration whilebeing washed with diethyl ether, whereby the title compound (596 mg) wasobtained as colorless foam.

[5961]¹H-NMR (DMSO-d₆) δ: 2.53-2.62 (3H, m), 2.63-2.74 (1H, m),2.90-3.06 (2H, m), 3.12-3.22 (0.5H, m), 3.39-3.59 (1.5H, s), 3.68-3.77(1H, m), 4.28 (1H, d, J=11.7 Hz), 4.28-4.50 (1.5H, m), 4.97 (0.5H, brs), 5.44 (0.5H, d, J=13.2 Hz), 6.13 (0.5H, br s), 7.72 (1H, dd, J=8.8,2.0 Hz), 7.80 (1H, d, J=8.8 Hz), 8.07-8.18 (2H, m), 8.22-8.27 (2H, m),8.50 (1H, s), 9.16-9.40 (1H, m).

[5962] MS (FAB) m/z: 534 [(M+H)⁺, Cl³⁵], 536 [(M+H)⁺, Cl³⁷].

Example B-974-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5963] In the same manner as in Example B-95, the title compound wasobtained.

[5964]¹H-NMR (CDCl₃) δ: 2.61-2.87 (1H, m), 2.88 (6H, br s), 2.89-3.24(3H, m), 3.45-3.90 (4H, m), 4.43-4.60 (3H, m), 4.74, 5.21 (total 1H,each br s), 5.60-6.09 (total 1H, m), 6.30, 6.42 (total 1H, br s), 7.58(1H, d, J=7.6 Hz), 7.80 (1H, d, J=9.0 Hz), 7.89-7.91 (3H, m), 8.35 (1H,s).

[5965] MS (FAB) m/z: 612 (M+H)⁺.

Example B-984-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-dimethylaminosulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[5966] In the same manner as in Example B-95, the title compound wasobtained.

[5967]¹H-NMR (DMSO-d₆) δ: 2.60-3.79 (25H, m), 4.38, 5.37 (total 1H, eachd, J=13.5, 14.5 Hz), 4.53 (2H, s), 5.04, 5.75(total 1H, each br), 7.02(1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.47 (1H, d, J=8.8 Hz), 7.76 (1H,s), 12.41 (1H, s).

[5968] MS (FAB) m/z: 700 (M+H)⁺.

Example B-994-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazineHydrochloride

[5969] To an ethanol solution (50 ml) of1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine(710 mg) was added a saturated ethanol hydrochloride solution (20 ml) atroom temperature. The resulting mixture was stirred for 3 hours. Afterconcentration of the reaction mixture under reduced pressure, diethylether and ethanol were added to precipitate crystals. The resultingcrystals were collected by filtration, washed with ethanol and thendried under reduced pressure. The crystals were dissolved inN,N-dimethylformamide to form an N,N-dimethylformamide solution (50 ml),followed by the addition of 1-hydroxybenzotriazole (68.8 mg),1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (115.4 mg),lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(189.0 mg) and N-methylmorpholine (140.5 mg) at room temperature. Theresulting mixture was stirred at room temperature for 19 hours. Thereaction solvent was distilled off under reduced pressure. Distilledwater and ethyl acetate were added to the residue and the water layerwas extracted three times. The organic layers were combined, washed fourtimes with distilled water, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue wassubjected to chromatography on a silica gel column (methanol:ethylacetate=1:50). Diethyl ether and methylene chloride were added to thepurified product to precipitate crystals. The resulting crystals werecollected by filtration, followed by washing with diethyl ether. A 1Naqueous hydrochloric acid in ethanol (0.5 ml) and a small amount ofdistilled water were added. The solvent was then distilled off underreduced pressure. The residue was dried under heat at 60° C. underreduced pressure, whereby the title compound (187 mg) was obtained as ayellow amorphous solid.

[5970] MS (FAB⁺) m/z: 607 [(M+H)⁺, Cl³⁵], 609 [(M+H)⁺, Cl³⁷].

[5971]¹H-NMR (DMSO-d₆) δ: 2.66-2.89 (1H, m), 2.99 (3H, s), 3.03-3.29(2H, m), 3.34-3.46 (1H, m), 3.52-3.92 (8H, m), 4.42-4.53 (1.5H, m),4.73-4.81 (1H, m), 5.10-5.17 (0.5H, m), 5.39-5.47 (1H, m), 5.82-5.92(0.5H, m), 7.12 (1H, br), 7.41 (1H, dd, J=2.0, 8.8 Hz), 7.58 (1H, d,J=8.8 Hz), 7.87 (1H, br), 12.57 (1H, s).

Example B-1002-(Carbamoylmethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5972] In the same manner as in Example B-98, the title compound wasobtained.

[5973] MS (FAB+) m/z: 537 [(M+H)⁺, Cl³⁵], 539 [(M+H)⁺, Cl³⁷].

[5974]¹H-NMR (DMSO-d₆) δ: 1.00-1.08 (1H, m), 2.65-2.68 (1H, m),2.88-2.94 (2H, m), 3.00-3.12 (1H, m), 3.27-3.46 (3H, m), 3.62-3.73 (1H,m), 4.32-4.39 (1H, m), 5.04-5.37 (1H, m), 6.83-6.86 (1H, m), 7.01 (1H,s), 7.27-7.33 (1H, m), 7.46 (1H, d, J=8.5 Hz), 7.76 (1H, s), 12.42 (1H,s).

Example B-1011-[(5-Chloroisoindolin-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylpiperazineHydrochloride

[5975] In the same manner as in Example B-62, the title compound wasobtained.

[5976] MS (FAB⁺) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

[5977]¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 3.08-3.19 (1H, m), 3.28-3.40 (8H,m), 3.40-3.53 (1H, br), 3.68-3.77 (2H, br), 4.28-4.46 (2H, m), 4.63-4.65(4H, m), 7.33 (1H, d, J=8.3 Hz), 7.37 (1H, dd, J=2.0, 8.3 Hz), 7.41 (1H,s).

Example B-1021-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothizolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5978] A saturated solution of hydrochloride in ethanol (8.0 ml) wasadded to1-(tert-butoxycarbonyl)-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine(300 mg). After stirring for 1 hour, the reaction mixture wasconcentrated under reduced pressure. To the residue were addedN,N-dimethylformamide (8.0 ml) and1-phenylsulfonyl-5-trimethylsilylethynylindol-2-sulfonyl chloride (450mg) at room temperature, followed by the addition ofdiisopropylethylamine (860 μl) at 0° C. After stirring at roomtemperature for 1 hour, the reaction mixture was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (methylene chloride:acetone:methanol=30:10:1→10:10:1),whereby4-[(6-methyl-4,5,6,7-tetrahydrothizolo[5,4-c]pyridin-2-yl)carbonyl]-1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl)carbonyl]piperazine(123 mg) was obtained as a colorless viscous substance. The resultingsubstance was dissolved in tetrahydrofuran (3.0 ml), followed by theaddition of methanol (3.0 ml) and potassium hydroxide (22.5 mg) at roomtemperature. After stirring for 2 hours, a saturated aqueous solution(10 ml) of ammonium chloride was added. A saturated aqueous solution (15ml) of sodium bicarbonate and methylene chloride (10 ml) were added andthe mixture was separated into layers. The water layer was extractedwith methylene chloride (10 ml). The organic layers were combined, driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was purified by preparative thin-layerchromatography (methylene chloride:acetone:methanol=40:10:1) usingsilica gel, whereby the title compound (39.4 mg) was obtained as acolorless solid. The resulting compound was dissolved in methylenechloride, methanol and water. The resulting solution was concentratedunder reduced pressure, followed by drying, whereby the title compoundwas obtained as a colorless solid.

[5979]¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.81 (2H, t, J=5.5 Hz), 2.90 (2H,t, J=5.5 Hz), 3.04 (1H, s), 3.22 (4H, br s), 3.68 (2H, s), 3.88 (2H, brs), 4.57 (2H, br s), 7.00 (1H, s), 7.37 (1H, d, J=8.6 Hz), 7.47 (1H, dd,J=8.6, 1.5 Hz), 7.86 (1H, s), 8.88 (1H, br s)

[5980] MS (FAB) m/z: 470 (M+H)⁺.

Example B-1032-(N-Methylcarbamoyl-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl)sulfonyl]piperazine

[5981] A saturated solution of hydrochloride in methanol (20 ml) wasadded to4-(tert-butoxycarbonyl)-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine(410 mg) at room temperature. After stirring for 1 hour, the reactionmixture was concentrated under reduced pressure. To the residue wereadded methylene chloride (15 ml) and1-phenylsulfonyl-5-trimethylsilylethynylindol-2-sulfonyl chloride (450mg) at room temperature, followed by the addition ofdiisopropylethylamine (590 μl) at room temperature. After stirring for12 hours, diisopropylethylamine (590 μl) was added again at roomtemperature. The resulting mixture was stirred at room temperature for 4hours. A saturated aqueous solution (50 ml) of sodium bicarbonate andmethylene chloride (50 ml) were added to the reaction mixture and themixture was separated into layers. The water layer was extracted withmethylene chloride (2×20 ml). The organic layers were combined, driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was purified by chromatography on asilica gel column (methylene chloride:methanol=20:1), whereby the titlecompound (389 mg) was obtained as a colorless transparent glassysubstance.

[5982]¹H-NMR (CDCl₃) δ: 0.25 (9H, s), 2.50 (3H, d, J=8.3 Hz), 2.65-3.02(8H, m), 3.05-3.30 (2H, m), 3.70 (2H, br s), 4.13 (1H, d, J=13.4 Hz),4.40 (1H, d, J=13.4 Hz), 4.67 (½H, d, J=13.4 Hz), 5.24 (½H, br s), 5.66(½H, d, J=14.0 Hz), 6.08 (½H, br s), 6.39 (1H, br s), 7.41 (2H, t, J=7.7Hz), 7.47-7.63 (3H, m), 7.71 (1H, s), 8.02 (2H, d, J=7.8 Hz), 8.18 (1H,d, J=8.8 Hz).

[5983] MS (FAB) m/z: 739 (M+H)⁺.

Example B-1044-[(5-Ethynylindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5984] In tetrahydrofuran (5.0 ml) was dissolved2-[(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl)carbonyl]piperazine(350 mg), followed by the addition of methanol (5.0 ml) and potassiumhydroxide (102 mg) at room temperature. After stirring for 4 hours, asaturated aqueous solution (50 ml) of sodium bicarbonate and methylenechloride (50 ml) were added to the reaction mixture to separate themixture into layers. The water layer was extracted with methylenechloride (50 ml). The organic layers were combined, dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue was purified twice by chromatography on a silicagel column (methylene chloride:methanol=20:1), whereby the titlecompound (126 mg) was obtained as a colorless solid. The resulting solidwas dissolved in methylene chloride, methanol and water, followed byconcentration under reduced pressure and drying, whereby the titlecompound was obtained as a colorless solid.

[5985]¹H-NMR (CDCl₃) δ: 2.51 (3H, s), 2.75-3.30 (11H, m), 3.58-3.85 (3H,m), 4.50-4.70 (2H, m), 5.25 (½H, brs), 5.64 (½H, d, J=11.5 Hz), 6.10(½H, br s), 6.53 (½H, br s), 7.10 (1H, s), 7.43 (2H, s), 7.85 (1H, s),10.78 (1H, d, J=9.5 Hz).

[5986] MS (FAB) m/z: 527 (M+H)⁺.

Example B-1051-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-yl)carbonyl]piperazineHydrochloride

[5987] In the same manner as in Example B-62, the title compound wasobtained.

[5988]¹H-NMR (DMSO-d₆) δ: 2.92 (3H, s), 3.04-3.28 (6H, m), 3.35-3.90(4H, m), 4.12-4.70 (4H, m), 7.69 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, dd,J=8.8, 2.0 Hz), 8.14 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.25 (1H, dd, dd,J=8.8, 2.0 Hz), 8.50 (1H, s), 11.27 (1H, br s).

[5989] MS (FAB) m/z: 491 [(M+H)⁺, Cl³⁵], 493 [(M+H)⁺, Cl³⁷].

Example B-1064-[(5-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5990] In the same manner as in Example B-62, the title compound wasobtained.

[5991]¹H-NMR (DMSO-d₆) δ: 2.43-2.81 (5H, m), 2.89-2.95 (4H, m),3.22-3.80 (6H, m), 4.16-4.65 (2.5H, m), 5.01 (0.5H, s), 5.36-5.45 (0.5H,m), 6.06 (0.5H, br s), 7.00 (1H, s), 7.29 (1H, d, J=8.8 Hz), 7.48 (1H,d, J=8.8 Hz), 7.75 (1H, s), 11.25-11.40 (1H, m), 12.43 (1H, s).

[5992] MS (FAB) m/z: 537 [(M+H)⁺, Cl³⁵], 539 [(M+H)⁺, Cl³⁷].

Example B-1074-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[5993] In the same manner as in Example B-62, the title compound wasobtained.

[5994]¹H-NMR (DMSO-d₆) δ: 1.31-1.40 (6H, m), 2.38-2.75 (5H, m),3.10-3.80 (8H, m), 4.22-4.50 (2.5H, m), 4.97 (½H, br s), 5.35-5.49 (½H,m), 6.13 (¼H, br s), 6.19 (¼H, br s), 7.70 (1H, d, J=8.8 Hz), 7.79 (1H,d, J=8.8 Hz), 8.09-8.28 (4H, m), 8.49 (1H, s), 10.80-11.34 (1H, m).

[5995] MS (FAB) m/z: 576 [(M+H)⁺, Cl³⁵], 578 [(M+H)⁺, Cl³⁷].

Example B-1081-[(5-Chloroindol-2-yl)sulfonyl]-4-[(thiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[5996] In the same manner as in Example B-62, the title compound wasobtained.

[5997]¹H-NMR (DMSO-d₆) δ: 3.20 (4H, br s), 3.84 (2H, br s), 4.35 (2H, brs), 7.28 (1H, dd, J=8.8, 2.5 Hz), 7.47 (1H, dd, J=8.8, 2.0 Hz), 7.74(1H, d, J=2.0 Hz), 8.05 (1H, d, J=5.4 Hz), 8.67 (1H, d, J=5.4 Hz), 9.44(1H, s), 12.41 (1H, s).

[5998] MS (FAB) m/z: 462 [(M+H)⁺, Cl³⁵], 464 [(M+H)⁺, Cl³⁷].

Example B-1092-[[4-[(5-Chloroindol-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methylthiazolo[5,4-c]pyridiniumIodide

[5999] In the same manner as in Example B-62, the title compound wasobtained.

[6000]¹H-NMR (DMSO-d₆) δ: 3.14-3.28 (4H, m), 3.86 (2H, br s), 4.29 (2H,br s), 4.49 (3H, s), 7.04 (1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.48(1H, d, J=8.8 Hz), 7.76 (1H, s), 8.72 (1H, d, J=6.8 Hz), 9.00 (1H, d,J=6.8 Hz), 9.94 (1H, s), 12.44 (1H, br s)

[6001] MS (FAB) m/z: 476, 478.

Example B-1101-[(6-tert-Butoxycarbonyl-7-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazineHydrochloride

[6002] In the same manner as in Example B-62, the title compound wasobtained.

[6003]¹H-NMR (DMSO-d₆) δ: 1.38 (3H, d, J=6.6 Hz), 1.42 (9H, s),2.55-2.80 (5H, m), 3.31 (3H, s), 3.46-3.56 (½H, m), 3.61-3.72 (1H, m),3.81-3.90 (1H, m), 4.18-4.29 (2H, m), 4.43-4.48 (½H, m), 4.91-5.05 (1H,m), 5.26-5.45 (1H, m), 6.15-6.25 (2H, m), 6.98-7.03 (1H, m), 7.26-7.33(1H, m), 7.41-7.50 (1H, m), 7.73-7.80 (1H, m), 8.02-8.17 (1H, m), 12.40(1H, s).

[6004] MS (FAB) m/z: 637 [(M+H)⁺, Cl³⁵], 639 [(M+H)⁺, Cl³⁷].

Example B-1114-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(7-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineTrifluoroacetate

[6005] In the same manner as in Example B-35, the title compound wasobtained.

[6006]¹H-NMR (DMSO-d₆) δ: 1.55 (3H, d, J=6.4 Hz), 2.28-2.76 (5H, m),2.88-3.10 (2H, m), 3.25-3.65 (1H, m), 4.20-4.30 (1H, m), 4.40-4.50 (½H,m), 4.83 (1H, br s), 4.92-5.02 (½H, m), 5.40-5.50 (½H, m), 6.13 (½H, s),7.00 (1H, s), 7.30 (1H, d, J=8.8 Hz), 7.46 (1H, d, J=8.8 Hz), 7.76 (1H,s), 8.06-8.14 (1H, m), 8.93-9.62 (2H, m), 12.40 (1H, s).

[6007] MS (FAB) m/z: 537 [(M+H)⁺, Cl³⁵], 539 [(M+H)⁺, Cl³⁷].

Example B-1124-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazineHydrochloride

[6008] In the same manner as in Example B-32, the title compound wasobtained.

[6009]¹H-NMR (DMSO-d₆) δ: 1.40-1.70 (3H, m), 2.40-2.80 (4H, m), 2.92(3H, br s), 3.00-3.25 (2H, m), 3.40-3.80 (1H, m), 4.19-4.30 (1H, m),4.39-4.50 (½H, m), 4.66-4.82 (½H, br s), 5.00 (½H, br s), 5.40-5.55 (½H,m), 5.73 (½H, br s), 6.17 (½H, br s), 7.00 (1H, s), 7.30 (1H, d, J=8.8Hz), 7.46 (1H, d, J=8.8 Hz), 7.76 (1H, s), 8.05-8.20 (1H, m), 12.41 (1H,s).

[6010] MS (EI) m/z: 550 (M⁺, Cl³⁵), 552 (M⁺, Cl³⁷)

Example B-1132-[N-[(5-Acetoxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6011] In the same manner as in Example B-62, the title compound wasobtained.

[6012]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.22 (3H, s), 2.38 (3H, s),2.65-2.89 (8H, m), 3.64 (2H, s), 3.70 (1H, d, J=11.0 Hz), 4.28 (1H, d,J=12.4 Hz), 6.30 (1H, s), 6.98 (1H, s), 7.26 (1H, dd, J=9.2, 1.8 Hz),7.46 (1H, d, J=9.2 Hz), 7.70 (1H, d, J=1.8 Hz), 8.28 (1H, s), 8.51 (1H,s), 12.00 (1H, br s).

[6013] MS (FAB) m/z: 689 [(M+H)⁺, Cl³⁵], 691 [(M+H)⁺, Cl³⁷].

Example B-1144-[(5-Chloroindol-2-yl)sulfonyl]-2-[N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6014] In the same manner as in Example B-23, the title compound wasobtained.

[6015]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.71-2.84 (1H, m), 2.90 (3H, s),3.00 (1H, dd, J=12.2, 4.3 Hz), 3.06-3.28 (4H, m), 3.54 (2H, br s), 3.74(1H, d, J=12.0 Hz), 4.09-4.28 (4H, m), 4.52 (2H, br s), 7.00 (1H, d,J=1.2 Hz), 7.29 (1H, dd, J=9.2, 1.8 Hz), 7.50 (1H, d, J=9.2 Hz), 7.73(1H, d, J=1.8 Hz), 7.91 (1H, s), 8.60 (1H, s), 12.14 (1H, br s).

[6016] MS (FAB) m/z: 647 [(M+H)⁺, Cl³⁵], 649 [(M+H)⁺, Cl³⁷].

Example B-115N-[[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]methanesulfonamideHydrochloride

[6017] In the same manner as in Example B-62, the title compound wasobtained.

[6018]¹H-NMR (DMSO-d₆) δ: 2.61-3.10 (8H, m), 3.15 (3H, s), 3.34-3.81(4H, m), 3.90-4.48 (2.5H, m), 4.60-4.72 (1H, m), 5.10 (0.5H, br s),5.29-5.39 (0.5H, m), 5.80-6.00 (0.5H, m), 7.02 (1H, s), 7.30 (1H, d,J=8.8 Hz), 7.48 (1H, d, J=8.8 Hz), 7.75 (1H, s), 11.45-11.70 (1H, m),11.85-12.00 (1H, m), 12.46 (1H, br s).

[6019] MS (FAB) m/z: 615 [(M+H)⁺, Cl³⁵], 617 [(M+H)⁺, Cl³⁷].

Example B-116N-[[1-[(6-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-2-yl]acetyl]methanesulfonamide

[6020] In the same manner as in Example B-62, the title compound wasobtained.

[6021]¹H-NMR (DMSO-d₆) δ: 1.40 (9H, s), 2.62-2.93 (6H, m), 3.09-3.20(3H, m), 3.40-3.50 (0.5H, m), 3.60-3.78 (4.5H, m), 4.35-4.43 (0.5H, m),4.61 (2H, s), 5.07-5.14 (0.5H, m), 5.30-5.40 (0.5H, m), 5.90-6.00 (0.5H,m), 7.03 (1H, s), 7.29 (1H, dd, J=8.8, 2.0 Hz), 7.45 (1H, d, J=8.8 Hz),7.74 (1H, s), 11.84 (1H, br s), 12.39 (1H, br s).

[6022] MS (FAB) m/z: 701 [(M+H)⁺, Cl³⁵], 703 [(M+H)⁺, Cl³⁷].

Example B-117N-[[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-1-yl]acetyl]methanesulfonamideTrifluoroacetate

[6023] In the same manner as in Example B-35, the title compound wasobtained.

[6024]¹H-NMR (DMSO-d₆) δ: 2.64-3.04 (6H, m), 3.15 (3H, d, J=7.1 Hz),3.41-3.53 (2H, m), 3.60-3.80 (4H, m), 4.35-4.43 (0.5H, m), 4.44 (2H, s),5.06-5.12 (0.5H, m), 5.25-5.35 (0.5H, m), 5.86 (0.5H, br s), 7.02 (1H,s), 7.29 (1H, dd, J=8.8, 2.0 Hz), 7.46 (1H, d, J=8.8 Hz), 7.75 (1H, s),9.25 (2H, br s), 11.86 (1H, br s), 12.42 (1H, br s).

[6025] MS (FAB) m/z: 601 [(M+H)⁺, Cl³⁵], 603 [(M+H)⁺, Cl³⁷].

Example B-118N-[[1-[[6-(1-Acetoxyethoxy)carbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazin-2-yl]acetyl]methanesulfonamide

[6026] In ethanol (2 ml) was dissolvedN-[[4-[(5-chloroindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]methanesulfonamidetrifluoroacetate (97 mg), followed by the addition of triethylamine(0.63 ml) and 1-acetoxyethyl p-nitrophenyl carbonate (110 mg). Theresulting mixture was stirred at room temperature for 4 hours. Thereaction mixture was concentrated under reduced pressure. Methylenechloride was added to the residue. The resulting mixture was washed withwater, dried over anhydrous sodium sulfate and distilled to remove thesolvent. The residue was purified by chromatography on a silica gelcolumn (methylene chloride:methanol=50:1), whereby the title compound(50 mg) was obtained as a colorless foam.

[6027]¹H-NMR (DMSO-d₆) δ: 1.42 (3H, br s), 2.01 (3H, br s), 2.60-2.90(6H, m), 3.07-3.16 (3H, m), 3.64-3.80 (4H, m), 4.09-4.12 (0.5H, m),4.35-4.41 (0.5H, m), 4.63-4.77 (2.5H, m), 5.05-5.11 (0.5H, m), 5.32-5.39(0.5H, m), 5.89-5.96 (0.5H, m), 6.62-6.70 (1H, m), 7.02 (1H, s), 7.29(1H, d, J=8.8 Hz), 7.46 (1H, d, J=8.8 Hz), 7.75 (1H, s), 11.88 (1H, brs), 12.44 (1H, br s).

[6028] MS (FAB) m/z: 731 [(M+H)⁺, Cl³⁵], 733 [(M+H)⁺, Cl³⁷].

Example B-1194-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6029] In the same manner as in Example B-62, the title compound wasobtained.

[6030]¹H-NMR (DMSO-d₆) δ: 2.62 (3H, s), 2.66-4.49 (13.5H, m), 4.60-4.76(1H, m), 5.05 (½H, br s), 5.50-5.62 (½H, m), 6.15-6.27 (½H, m), 7.57(1H, d, J=8.8 Hz), 8.07 (1H, d, J=8.8 Hz), 8.08 (1H, s), 8.17 (½H, brs), 8.23 (½H, br s), 8.37 (1H, s).

[6031] MS (FAB) m/z: 554 [(M+H)⁺, Cl³⁵], 556 [(M+H)⁺, Cl³⁷].

Example B-1204-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(thiazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[6032] In the same manner as in Example B-62, the title compound wasobtained.

[6033]¹H-NMR (CDCl₃) δ: 3.27 (4H, br s), 3.90-4.03 (2H, m), 4.61-4.73(2H, m), 7.58 (1H, dd, J=8.8, 2.0 Hz), 7.79 (1H, dd, J=8.8, 2.0 Hz),7.85-8.01 (4H, m), 8.34 (1H, s), 8.59 (1H, d, J=5.4 Hz), 9.35 (1H, d,J=1.0 Hz).

[6034] MS (FAB) m/z: 473 [(M+H)⁺, Cl³⁵], 475 [(M+H)⁺, Cl³⁷].

Example B-1212-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]thiazolo[4,5-c]pyridineN-Oxide

[6035] In the same manner as in Example B-34, the title compound wasobtained.

[6036]¹H-NMR (DMSO-d₆) δ: 3.15 (4H, br s), 3.80 (2H, br s), 4.32 (2H, brs), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.83 (1H, dd, J=8.8, 2.0 Hz), 8.15(1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.25 (1H, d,J=8.8 Hz), 8.30 (1H, d, J=2.0 Hz), 8.32 (1H, d, J=1.5 Hz), 8.51 (1H, s),9.03 (1H, d, J=1.5 Hz).

[6037] MS (FAB) m/z: 489 [(M+H)⁺, Cl³⁵], 491 [(M+H)⁺, Cl³⁷].

Example B-1222-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-5-methylthiazolo[4,5-c]pyridiniumIodide

[6038] In the same manner as in Example B-33, the title compound wasobtained.

[6039]¹H-NMR (DMSO-d₆) δ: 3.10-3.25 (4H, m), 3.85 (2H, br s), 4.29 (2H,br s), 4.47 (3H, s), 7.71 (1H, dd, J=8.8, 2.0 Hz), 7.84 (1H, d, J=8.8Hz), 8.17 (1H, d, J=8.8 Hz), 8.23 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.53(1H, s), 8.86 (1H, d, J=6.8 Hz), 8.90 (1H, d, J=6.8 Hz), 10.03 (1H, s).

[6040] MS (FAB) m/z: 487, 489.

Example B-1234-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(thiazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine

[6041] In the same manner as in Example B-62, the title compound wasobtained.

[6042]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.61 (3H, d, J=4.9 Hz), 2.75-2.88(1H, m), 2.98 (1H, dd, J=12.7, 4.9 Hz), 3.20-3.80 (1H, m), 4.29 (1H, d,J=2.7 Hz), 4.90-5.48 (1H, m), 7.61 (1H, dd, J=8.8, 2.0 Hz), 7.79 (1H, brs), 7.81 (1H, dd, J=8.8, 2.0 Hz), 8.04-8.10 (2H, m), 8.12 (1H, d, J=5.4Hz), 8.15 (1H, d, J=8.8 Hz), 8.44 (1H, d, J=1.0 Hz), 8.56 (1H, d, J=5.4Hz), 9.28 (1H, br s).

[6043] MS (FAB) m/z: 530 [(M+H)⁺, Cl³⁵], 532 [(M+H)⁺, Cl³⁷].

Example B-1242-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazin-1-yl]carbonyl]-5-methylthiazolo[4,5-c]pyridiniumIodide

[6044] In the same manner as in Example B-33, the title compound wasobtained.

[6045]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.62 (3H, d, J=4.4 Hz), 2.77-2.87(1H, m), 2.94-3.03 (1H, m), 3.10-3.90 (2H, m), 4.31 (1H, d, J=12.7 Hz),4.50 (3H, s), 4.85-5.85 (2H, m), 7.64 (1H, dd, J=8.8, 2.0 Hz), 7.80 (1H,dd, J=8.8, 2.0 Hz), 7.82-7.90 (1H, m), 8.10 (1H, d, J=8.8 Hz), 8.12 (1H,d, J=2.0 Hz), 8.17 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.86 (2H, d, J=1.5Hz), 9.93 (1H, br s).

[6046] MS (FAB) m/z: 544 (M⁺, Cl³⁵), 546 (M⁺, Cl³⁷).

Example B-1254-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6047] The title compound was obtained in the same manner as inReferential Example 404 in which reduction by sodium borohydride hadbeen employed.

[6048]¹H-NMR (DMSO-d₆) δ: 2.41-2.80 (5H, m), 3.12-3.78 (7H, m),4.15-4.60 (2.5H, m), 4.97 (0.5H, br s), 5.35-5.48 (0.5H, m), 6.03 (0.5H,br s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.79 (1H, d, J=8.8 Hz), 8.06-8.20(2H, m), 8.22 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.48 (1H, s), 11.20-11.63(1H, m).

[6049] MS (FAB) m/z: 548 [(M+H)⁺, Cl³⁵], 550 [(M+H)⁺, Cl³⁷].

Example B-1264-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-ethyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)carbonyl-2-(N-methylcarbamoyl)piperazineHydrochloride

[6050] In the same manner as in Referential Example 404, the titlecompound was obtained.

[6051]¹H-NMR (DMSO-d₆) δ: 1.28-1.40 (3H, m), 2.40-2.79 (5H, m),3.10-3.83 (10H, m), 4.15-4.60 (2.5H, m), 4.97 (0.5H, br s), 5.35-5.45(0.5H, m), 6.05-6.12 (0.5H, m), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.79 (1H,d, J=8.8 Hz), 8.05-8.17 (2H, m), 8.22 (1H, s), 8.24 (1H, d, J=8.8 Hz),8.49 (1H, s), 11.01-11.20 (1H, m).

[6052] MS (FAB) m/z: 562 [(M+H)⁺, Cl³⁵], 564 [(M+H)⁺, Cl³⁷].

Example B-127 tert-Butyl[2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)acetate

[6053] In N,N-dimethylformamide (50 ml) was dissolved1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (240 mg), followed by the addition of triethylamine (0.28ml) and then tert-butyl bromoacetate (0.14 ml). The resulting mixturewas stirred overnight at room temperature. After concentration of thereaction mixture under reduced pressure, ethyl acetate was added to theresidue. The resulting mixture was washed with water, dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by chromatography on a silica gelcolumn (Φ 3.0×12.0 cm, hexane:ethyl acetate=3:2), whereby the titlecompound (207 mg) was obtained as a colorless foam.

[6054]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.86-2.92 (2H, m), 3.00 (2H, t,J=5.4 Hz), 3.18 (4H, br s), 3.35 (2H, s), 3.87 (2H, br s), 3.90 (2H, s),4.55 (2H, br s), 7.57 (1H, dd, J=8.8, 2.0 Hz), 7.76 (1H, dd, J=8.8, 2.0Hz), 7.87-7.93 (3H, m), 8.31 (1H, s).

[6055] MS (FAB) m/z: 591 [(M+H)⁺, Cl³⁵], 593 [(M+H)⁺, Cl³⁷].

Example B-128 Ethyl[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)acetate

[6056] In the same manner as in Example B-127, the title compound wasobtained.

[6057]¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.3 Hz), 2.85-2.95 (2H, m),2.97-3.07 (2H, m), 3.18 (4H, br s), 3.46 (2H, s), 3.87 (2H, br s), 3.92(2H, s), 4.20 (2H, q, J=7.3 Hz), 4.55 (2H, br s), 7.57 (1H, d, J=8.8Hz), 7.76 (1H, d, J=8.8 Hz), 7.82-7.95 (3H, m), 8.31 (1H, s).

[6058] MS (FAB) m/z: 477 [(M+H)⁺, Cl³⁵], 479 [(M+H)⁺, Cl³⁷].

Example B-129[2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)aceticAcid Trifluoroacetate

[6059] In methylene chloride (1 ml) was dissolved tert-butyl[2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)acetate(200 mg), followed by the addition of trifluoroacetic acid (2 ml). Theresulting mixture was stirred at room temperature for 2 hours. Afterconcentration under reduced pressure, diethyl ether was added to theresidue. The precipitate so formed was collected by filtration, wherebythe title compound (193 mg) was obtained as a colorless foam.

[6060]¹H-NMR (DMSO-d₆) δ: 2.96 (2H, br s), 3.08 (4H, br s), 3.27-3.96(6H, m), 4.37 (4H, br s), 7.70 (1H, dd, J=8.8, 2.0 Hz), 7.82 (1H, d,J=8.8 Hz), 8.20-8.28 (3H, m), 8.50 (1H, s).

[6061] MS (FAB) m/z: 535 [(M+H)⁺, Cl³⁵], 537 [(M+H)⁺, Cl³⁷].

Example B-130N-[[2-[[4-(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl]acetyl]methanesulfonamideHydrochloride

[6062] In tetrahydrofuran (20 ml) was dissolved[2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl]aceticacid trifluoroacetate (110 mg), followed by the addition ofcarbonyldiimidazole (60 mg). The resulting mixture was heated underreflux for 1 hour. After the reaction was cooled to room temperature,methanesulfonamide (34 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.05ml) were added and they were stirred for 30 minutes. The reactionmixture was concentrated under reduced pressure. To the residue wasadded methylene chloride, followed by washing with water, 0.2Nhydrochloric acid and saturated aqueous NaCl solution, each once. Theorganic layer thus extracted was dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by chromatography on a silica gel column (methylenechloride:methanol=100:4), whereby colorless foam was obtained. Theresulting foam was suspended in a 1N aqueous hydrochloric acid inethanol solution (1 ml), followed by concentration under reducedpressure and azeotropy with water, whereby the title compound (44 mg)was obtained as pale yellow foam.

[6063]¹H-NMR (DMSO-d₆) δ: 3.00 (2H, br s), 3.11 (4H, br s), 3.28 (3H,s), 3.32-4.06 (6H, m), 4.40 (4H, br s), 7.70 (1H, dd, J=8.8, 2.0 Hz),7.82 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.25 (1H,d, J=8.8 Hz), 8.50 (1H, s).

[6064] MS (FAB) m/z: 612 [(M+H)⁺, Cl³⁵], 614 [(M+H)⁺, Cl³⁷].

Example B-131 Ethyl[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]piperazin-1-yl]acetateHydrochloride

[6065] In the same manner as in Example B-62, the title compound wasobtained.

[6066]¹H-NMR (DMSO-d₆ at 100° C.) δ: 1.26 (3H, t, J=7.2 Hz), 2.80-3.35(13H, m) 3.44-3.89 (11H, m), 4.20 (2H, q, J=7.2 Hz), 4.52 (2H, br s),7.67 (1H, dd, J=8.8, 1.7 Hz), 7.81 (1H, d, J=8.8, 1.7 Hz), 8.11 (1H, d,J=8.8 Hz), 8.16 (1H, s), 8.19 (1H, d, J=8.8 Hz), 8.47 (1H, s).

[6067] MS (FAB) m/z: 689 [(M+H)⁺, Cl³⁵], 691 [(M+H)⁺, Cl³⁷].

Example B-132[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]piperazin-1-yl]aceticacid Hydrochloride

[6068] In the same manner as in Example B-23, the title compound wasobtained.

[6069]¹H-NMR (DMSO-d₆ at 100° C.) δ: 2.84-2.93 (5H, m), 3.10-3.34 (7H,m), 3.45-3.61 (2H, m), 3.70-4.70 (12H, m), 7.67 (1H, dd, J=8.8, 2.0 Hz),7.81 (1H, d, J=8.8, 1.7 Hz), 8.11 (1H, d, J=8.8 Hz), 8.17 (1H, s), 8.20(1H, d, J=8.8 Hz), 8.48 (1H, s).

[6070] MS (FAB) m/z: 661 [(M+H)⁺, Cl³⁵], 663 [(M+H)⁺, Cl³⁷].

Example B-133N-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]methanesulfonamideHydrochloride

[6071] In tetrahydrofuran (30 ml) was dissolved2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)carbonyl]piperazine(300 mg), followed by the addition of a 0.5 mole toluene solution (1.12ml) of potassium bis(trimethylsilyl)amide. The resulting mixture wasstirred for 10 minutes under ice cooling. After the addition ofmethanesulfonyl chloride (0.04 ml), the resulting mixture was warmed upto room temperature and stirred for 1 hour. The reaction mixture wasconcentrated under reduced pressure. Methylene chloride was added to theresidue and the resulting mixture was washed once with water and oncewith saturated aqueous NaCl solution. The organic layer thus extractedwas dried over anhydrous sodium sulfate and distilled under reducedpressure to remove the solvent. The residue was purified bychromatography on a silica gel column (methylenechloride:methanol=100:0→100:3), whereby colorless foam was obtained. Theresulting foam was suspended in 1N hydrochloric acid (1 ml). Theresulting suspension was concentrated under reduced pressure, wherebythe title compound (96 mg) was obtained as pale yellow foam.

[6072]¹H-NMR (DMSO-d₆) δ: 2.73-2.84 (1H, m), 2.90 (6H, s), 3.09-3.77(8H, m), 3.99-4.27 (1H, m), 4.39-4.51 (1H, m), 4.69-4.79 (1H, m), 4.99(1H, s), 7.64-7.73 (2H, m), 8.06-8.10 (1H, m), 8.12-8.19 (1H, m), 8.44(1H, s), 11.41 (1H, br s), 11.52 (1H, s).

[6073] MS (FAB) m/z: 612 [(M+H)⁺, Cl³⁵], 614 [(M+H)⁺, Cl³⁷].

Example B-1345-[2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]tetrazoleTrifluoroacetate

[6074] In N,N-dimethylformamide (10 ml) were dissolved lithium6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(329 mg),5-[2-[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-2-yl]ethyl]tetrazoletrifluoroacetate (295 mg), 1-hydroxybenzotriazole monohydrate (9 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg),followed by stirring overnight at room temperature. The reaction mixturewas concentrated under reduced pressure. Methylene chloride was added tothe residue and the resulting mixture was washed with water andsaturated aqueous NaCl solution, each once. The organic layer was thendried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (methylene chloride:methanol=25:2), whereby paleyellow foam (48 mg) was obtained. The resulting foam was dissolved inmethylene chloride (1 ml), followed by the addition of trifluoroaceticacid (1 ml). After concentration under reduced pressure, the precipitateso formed was collected by filtration while being washed with diethylether, whereby the title compound (48 mg) was obtained as a colorlesssolid.

[6075]¹H-NMR (DMSO-d₆) δ: 1.12-1.40 (2H, m), 1.95-3.00 (7H, m),3.42-3.47 (1H, m), 3.60-3.88 (2.5H, m), 4.10-4.15 (0.5H, br s),4.38-4.45 (2H, m), 4.67-4.80 (1H, m), 5.25-5.31 (0.5H, m), 5.58-5.65(0.5H, m), 7.70 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=8.8 Hz), 8.14 (1H, d,J=8.8 Hz), 8.18-8.26 (2H, m), 8.46-8.50 (1H, m).

[6076] MS (FAB) m/z: 573 [(M+H)⁺, Cl³⁵], 575 [(M+H)⁺, Cl³⁷].

Example B-1355-[2-[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]ethyl]tetrazole

[6077] In the same manner as in Example B-32, the title compound wasobtained.

[6078]¹H-NMR (DMSO-d₆) δ: 1.08-1.40 (2H, m), 1.90-3.84 (15.5H, m), 4.10(0.5H, br s), 4.32-4.43 (0.5H, m), 4.72-4.80 (0.5H, m), 5.35-5.43 (0.5H,m), 5.69-5.80 (0.5H, m), 7.68 (1H, dd, J=8.8, 2.0 Hz).

[6079] MS (FAB) m/z: 587 [(M+H)⁺, Cl³⁵], 589 [(M+H)⁺, Cl³⁷].

Example B-1365-[[[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]amino]methyl]tetrazoleTrifluoroacetate

[6080] In the same manner as in Example B-134, the title compound wasobtained.

[6081]¹H-NMR (DMSO-d₆) δ: 2.63-2.78 (1H, m), 2.85-2.93 (1H, m),2.99-3.05 (1H, m), 3.28-3.79 (6H, m), 4.27-4.34 (1H, m), 4.40-4.70(3.5H, m), 5.13-5.16 (0.5H, m), 5.48-5.56 (0.5H, m), 6.10-6.13 (0.5H,m), 7.70 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=8.8 Hz), 8.08-8.26 (3H, m),8.48 (1H, s), 8.89-9.00 (1H, m).

[6082] MS (FAB) m/z: 602 [(M+H)⁺, Cl³⁵], 604 [(M+H)⁺, Cl³⁷].

Example B-1375-[[[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]carbonyl]amino]methyl]tetrazole

[6083] In the same manner as in Example B-32, the title compound wasobtained.

[6084]¹H-NMR (DMSO-d₆) δ: 2.36 (3H, s), 3.59 (1H, d, J=12.2 Hz),3.65-3.75 (1H, m), 4.16-4.56 (4.5H, m), 5.06 (0.5H, br s), 5.48-5.57(0.5H, m), 6.20 (0.5H, br s), 7.67 (1H, dd, J=8.8, 2.0 Hz), 7.80 (1H, d,J=8.8 Hz), 8.05-8.35 (4H, m), 8.49 (1H, s).

Example B-1382-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]methyl]-4,5-dihydro-5-oxo-1,3,4-oxadiazoleTrifluoroacetate

[6085] In the same manner as in Example B-134, the title compound wasobtained.

[6086]¹H-NMR (DMSO-d₆) δ: 2.38-2.69 (2H, m), 2.92-3.11 (3H, m),3.18-3.34 (1H, m), 3.40-3.88 (5H, m), 4.39-4.47 (2.5H, m), 4.99 (0.5H,br s), 5.38-5.44 (0.5H, m), 5.72-5.88 (0.5H, br s), 7.70 (1H, d, J=8.8Hz), 7.81 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.24(1H, d, J=8.8 Hz), 8.50 (1H, s), 9.23 (2H, br s), 12.03 (0.5H, s), 12.08(0.5H, s).

[6087] MS (FAB) m/z: 575 [(M+H)⁺, Cl³⁵], 577 [(M+H)⁺, Cl³⁷].

Example B-1392-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]methyl]-4,5-dihydro-5-oxo-1,3,4-oxadiazole

[6088] In the same manner as in Example B-32, the title compound wasobtained.

[6089]¹H-NMR (DMSO-d₆) δ: 2.35 (3H, s), 2.37-2.82 (6H, m), 2.97-3.36(2.5H, m), 3.45-3.88 (4.5H, m), 4.40-4.46 (0.5H, m), 4.98 (0.5H, br s),5.45-5.55 (0.5H, br s), 5.93 (0.5H, br s), 7.70 (1H, dd, J=8.8, 2.0 Hz),7.81 (1H, dd, J=8.8, 2.0 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.24(1H, d, J=8.8 Hz), 8.50 (1H, s), 11.91-12.10 (1H, m).

[6090] MS (FAB) m/z: 589 [(M+H)⁺, Cl³⁵], 591 [(M+H)⁺, Cl³⁷].

Example B-1404-[(5-Chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6091] In the same manner as in Example B-1, the title compound wasobtained.

[6092]¹H-NMR (DMSO-d₆) δ: 2.33-3.85 (19H, m), 4.35-4.50 (2.5H, m),5.01-5.08 (0.5H, m), 5.27-5.37 (0.5H, m), 5.68-5.78 (0.5H, m), 7.03 (1H,s), 7.32 (1H, d, J=8.8 Hz), 7.48 (1H, d, J=8.8 Hz), 7.77 (1H, s), 9.54(2H, br s), 12.45 (1H, s).

[6093] MS (FAB) m/z: 593 [(M+H)⁺, Cl³⁵], 595 [(M+H)⁺, Cl³⁷].

Example B-1411-[[6-(1-Acetoxyethoxy)carbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[6094] In ethanol (6 ml) was dissolved4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazinehydrochloride (200 mg), followed by the addition ofdiisopropylethylamine (83 μl) and 1-acetoxyethyl p-nitrophenyl carbonate(128 mg). The resulting mixture was stirred at room temperature for 5hours. The solvent was distilled off under reduced pressure. Methylenechloride and an aqueous solution of sodium bicarbonate were added andthe mixture was separated into layers. The organic layer was dried overanhydrous sodium sulfate and the filtrate was concentrated. The residuewas purified by chromatography on a silica gel column (1-2%methanol—methylene chloride). The product was dissolved in ethylacetate, followed by crystallization from diethyl ether, whereby thetitle compound (100 mg) was obtained as colorless powder.

[6095]¹H-NMR (DMSO-d₆) δ: 1.43 (3H, br s), 2.00-2.03 (3H, m), 2.30-3.80(19H, m), 4.35-4.45 (0.5H, m), 4.61-4.77 (2H, m), 5.01-5.08 (0.5H, m),5.27-5.37 (0.5H, m), 5.71-5.82 (0.5H, m), 6.65-6.68 (1H, m), 7.01 (1H,s), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=8.8 Hz), 7.75 (1H, s), 12.40(1H, s).

[6096] MS (FAB) m/z: 723 [(M+H)⁺, Cl³⁵], 725 [(M+H)⁺, Cl³⁷].

Example B-1421-[[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[6097] In the same manner as in Example B-62, the title compound wasobtained.

[6098]¹H-NMR (DMSO-d₆) δ: 1.41 (9H, s), 2.43-2.85 (5H, m), 3.15-3.75(6H, m), 4.20-4.27 (1H, m), 4.40-4.48 (0.5H, m), 4.60-4.67 (2H, m), 5.01(0.5H, s), 5.52-5.57 (0.5H, m), 6.19 (0.5H, br s), 6.99-7.01 (1H, m),7.30 (1H, d, J=8.8 Hz), 7.44-7.48 (1H, m), 7.76 (1H, s), 8.04-8.12 (1H,m), 12.39 (1H, s).

[6099] MS (FAB) m/z: 623 [(M+H)⁺, Cl³⁵], 625 [(M+H)⁺, Cl³⁷].

Example B-1434-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6100] In the same manner as in Example B-1, the title compound wasobtained.

[6101]¹H-NMR (DMSO-d₆) δ: 2.43-2.75 (5H, m), 2.95 (1H, br s), 3.02 (1H,br s), 3.15-3.25 (0.5H, m), 3.38-3.50 (2H, m), 3.50-3.62 (0.5H, m),3.63-3.75 (1H, m), 4.20-4.27 (1H, m), 4.35-4.50 (2.5H, m), 5.00 (0.5H,br s), 5.42-5.53 (0.5H, m), 6.15 (0.5H, br s), 7.01 (1H, s), 7.30 (1H,d, J=8.8 Hz), 7.47 (1H, d, J=8.8 Hz), 7.77 (1H, s), 8.09-8.14 (1H, m),9.43 (1H, br s), 12.42 (1H, s)

[6102] MS (FAB) m/z: 523 [(M+H)⁺, Cl³⁵], 525 [(M+H)⁺, Cl³⁷].

Example B-1444-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazine

[6103] In methylene chloride (25 ml) were dissolved4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine(209 mg) and benzoyl peroxide (70%, 138 mg) at room temperature,followed by heating under reflux for 9 hours. By the purification bychromatography on a silica gel column (4% methanol—methylene chloride),a crudely purified product of1-[(6-benzoyloxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine(190 mg) was obtained as a colorless glassy solid. The resulting solidwas dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol(20 ml), followed by the addition of a 1N aqueous solution (2.00 ml) ofsodium hydroxide. The resulting mixture was stirred at room temperaturefor 10 minutes. The solvent was distilled off and the residue wasseparated into layers by the addition of chloroform and water. Theorganic layer was dried over anhydrous sodium sulfate and the filtratewas concentrated. The residue was purified by preparative thin-layerchromatography (4% methanol—methylene chloride) using silica gel,whereby the title compound (19 mg) was obtained as colorless powder.

[6104]¹H-NMR (CDCl₃) δ: 2.75-3.25 (7H, m), 3.34 (2H, br s), 3.58-3.68(1H, m), 4.05-4.45 (2H, br), 4.53-4.73 (2H, m), 5.25 (0.5H, br s),5.50-5.75 (2.5H, m), 6.11 (0.5H, br s), 6.50 (0.5H, s), 7.05 (1H, br s),7.25-7.32 (1H, m), 7.35-7.45 (1H, m), 7.64 (1H, s), 10.73 (1H, s).

[6105] HRMS (FAB) m/z: 539.0920 (M+H)⁺ (calcd for C₂₁H₂₄ClN₆O₅S₂,539.0938).

Example B-1454-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6106] In the same manner as in Example B-94, the title compound wasobtained.

[6107]¹H-NMR (DMSO-d₆) δ: 2.40-2.85 (7H, m), 2.89 (3H, s), 3.00-3.30(3H, br), 3.40-3.82 (4H, m), 4.30-4.80 (2.5H, br), 5.06 (0.5H, br s),5.26-5.40 (0.5H, m), 5.81 (0.5H, br s), 7.02 (1H, s), 7.31 (1H, d, J=8.6Hz), 7.48 (1H, d, J=8.6 Hz), 7.76 (1H, s), 7.89-7.94 (1H, m), 11.16 (1H,br s), 12.44 (1H, s).

[6108] MS (FAB) m/z: 551 [(M+H)⁺, Cl³⁵], 553 [(M+H)⁺, Cl³⁷].

Example B-1464-[(5-Chloroindol-2-yl)sulfonyl]-2-[(methoxycarbonyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6109] In the same manner as in Example B-62, the title compound wasobtained.

[6110]¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.50-2.90 (7H, m), 2.95-3.06 (1H,m), 3.10-3.25 (0.5H, m), 3.35-3.50 (0.5H, m), 3.50-3.70 (5H, m),3.70-3.95 (2H, br), 4.60-4.64 (0.5H, br), 5.22 (0.5H, br s), 5.71-5.75(0.5H, m), 6.18 (0.5H, br s), 6.96 (1H, s), 7.31 (1H, dd, J=8.8, 1.7Hz), 7.36 (1H, d, J=8.8 Hz), 7.65 (1H, d, J=1.7 Hz), 9.15-9.20 (1H, br).

[6111] MS (FAB) m/z: 552 [(M+H)⁺, Cl³⁵], 554 [(M+H)⁺, Cl³⁷].

Example B-1472-(Carboxymethyl)-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6112] In the same manner as in Example B-77, the title compound wasobtained.

[6113]¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.40-3.81 (13H, m), 4.36-4.41(0.5H, br), 5.01 (0.5H, br s), 5.41-5.44 (0.5H, m), 5.86 (0.5H, br s),7.03 (1H, s), 7.31 (1H, dd, J=8.8, 1.7 Hz), 7.47 (1H, d, J=8.8 Hz), 7.76(1H, d, J=1.7 Hz), 12.42 (1H, s).

[6114] MS (FAB) m/z: 538 [(M+H)⁺, Cl³⁵], 540 [(M+H)⁺, Cl³⁷].

Example B-1484-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-[(1,3-dioxolan-2-yl)methyl]carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6115] In the same manner as in Example B-79, the title compound wasobtained.

[6116]¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 2.51-3.10 (7H, m), 3.30-3.65 (3H,m), 3.68 (2H, s), 3.70-4.12 (6H, m), 4.46-4.57 (0.5H, m), 4.90-5.00 (1H,m), 5.10-5.20 (0.5H, m), 5.55-5.70 (0.5H, m), 5.87 (0.5H, s), 6.28(0.5H, s), 6.52 (0.5H, s), 6.99 (1H, s), 7.28 (1H, d, J=8.8 Hz), 7.37(1H, d, J=8.8 Hz), 7.64 (1H, s), 10.38 (0.5H, br s), 10.62 (0.5H, s).

[6117] MS (FAB) m/z: 623 [(M+H)⁺, Cl³⁵], 625 [(M+H)⁺, Cl³⁷].

Example B-1491-[[4-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl)acetyl]piperidin-4-oneEthyleneketal

[6118] In the same manner as in Example B-79, the title compound wasobtained.

[6119]¹H-NMR (CDCl₃) δ: 1.60 (4H, s), 2.49 (3H, s), 2.55-3.20 (7H, m),3.20-3.35 (0.5H, m), 3.50-3.85 (8H, m), 4.00 (5H, br s), 4.12-4.23(0.5H, m), 4.55-4.67 (0.5H, m), 4.95-5.07 (0.5H, m), 5.45-5.60 (0.5H,m), 5.95-6.07 (0.5H, m), 7.00 (1H, s), 7.22-7.31 (1H, m), 7.37 (1H, d,J=8.8 Hz), 7.64 (1H, s), 10.37 (0.5H, br s), 11.14 (0.5H, s)

[6120] MS (FAB) m/z: 663 [(M+H)⁺, Cl³⁵], 665 [(M+H)⁺, Cl³⁷].

Example B-1504-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N,N-dimethylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6121] In the same manner as in Example B-79, the title compound wasobtained.

[6122]¹H-NMR (DMSO-d₆) δ: 2.40-2.80 (6H, m), 2.81-3.20 (9H, m),3.35-3.85 (5H, m), 4.30-4.80 (2.5H, br), 5.00 (0.5H, br s), 5.26-5.40(0.5H, m), 5.75 (0.5H, br s), 7.01 (1H, s), 7.30 (1H, d, J=8.6 Hz), 7.47(1H, d, J=8.6 Hz), 7.75 (1H, s), 11.22 (1H, br s), 12.42 (1H, s).

[6123] MS (FAB) m/z: 565 [(M+H)⁺, Cl³⁵], 567 [(M+H)⁺, Cl³⁷].

Example B-1514-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-(2,2-diethoxyethyl)carbamoyl]methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6124] In the same manner as in Example B-79, the title compound wasobtained.

[6125]¹H-NMR (CDCl₃) δ: 1.15-1.27 (6H, m), 2.50 (3H, s), 2.55-3.10 (8H,m), 3.30-3.90 (10H, m), 4.00-4.15 (1H, m), 4.45-4.60 (1.5H, m), 5.12(0.5H, br s), 5.55-5.70 (0.5H, m), 5.82 (0.5H, br s), 6.19 (0.5H, br s),6.59 (0.5H, br s), 7.01 (1H, s), 7.22-7.31 (1H, m), 7.36 (1H, d, J=9.0Hz), 7.65 (1H, s), 10.21 (0.5H, br s), 10.72 (0.5H, s).

[6126] MS (FAB) m/z: 653 [(M+H)⁺, Cl³⁵], 655 [(M+H)⁺, Cl³⁷].

Example B-1524-[(5-Chloroindol-2-yl)sulfonyl]-1-[(−6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[N(tetrahydrofurfuryl)carbamoyl]methyl]piperazineHydrochloride

[6127] In the same manner as in Example B-62, the title compound wasobtained.

[6128]¹H-NMR (DMSO-d₆) δ: 1.40-1.55 (1H, m), 1.65-1.90 (3H, m),2.40-2.89 (3H, br), 2.90 (3H, s), 3.00-3.40 (5H, m), 3.41-3.85 (9H, m),4.25-4.70 (1.5H, m), 5.08 (0.5H, br s), 5.26-5.37 (0.5H, m), 5.83 (0.5H,br s), 7.03 (1H, s), 7.31 (1H, d, J=9.0 Hz), 7.48 (1H, d, J=9.0 Hz),7.77 (1H, s), 8.07 (1H, br s), 11.00-11.30 (1H, br), 12.43 (1H, s).

[6129] MS (FAB) m/z: 621 [(M+H)⁺, Cl³⁵], 623 [(M+H)⁺, Cl³⁷].

Example B-1531-[[6-(tert-Butoxycarbonylaminosulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[6130] To methylene chloride (3 ml) was added tert-butyl alcohol (53mg). While cooling to 0° C., chlorosulfonylisocyanate (88 mg) was addedto the resulting mixture, followed by stirring for 10 minutes. To thereaction mixture was added a solution of4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]]piperazine(300 mg) and triethylamine (475 mg) in methylene chloride (3 ml). Afterstirring at room temperature for 1 hour, water was added to the reactionmixture and the resulting mixture was extracted with methylene chloride.The organic layer was dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby column chromatography (methanol:methylene chloride=1:19) using as acarrier silica gel, whereby the title compound (311 mg) was obtained. Aportion of the compound was purified further by preparative thin-layerchromatography (methanol:methylene chloride=1:9) using silica gel,followed by the addition of ether. The instrumental data on theresulting pale yellow solid was as follows:

[6131]¹H-NMR (DMSO-d₆) δ: 1.23, 1.24(total 9H, each s), 2.33-3.75 (19H,m), 4.37-5.86 (4H, m), 7.03 (1H, s), 7.31 (1H, d, J=8.8 Hz), 7.47 (1H,d, J=8.8 Hz), 7.76 (1H, s), 11.21 (1H, s), 12.42 (1H, s).

[6132] MS (FAB) m/z: 772 (M+H)⁺.

Example B-1541-[[6-(Aminosulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[6133] In methylene chloride (3 ml) was dissolved1-[[6-(tert-butoxycarbonylaminosulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine(275 mg), followed by the addition of trifluoroacetic acid (3 ml). Theresulting mixture was stirred at room temperature for 30 minutes. Thesolvent was distilled off under reduced pressure. A saturated solutionof hydrochloride in ethanol (3 ml) was added and the resulting mixturewas stirred at room temperature for 1.5 hours. The residue obtained bydistilling off the solvent under reduced pressure was added withmethylene chloride and water to separate into layers. The water layerwas extracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by preparative thin-layerchromatography (methanol:methylene chloride=1:9) using silica gel. Thesolid thus obtained was dissolved in a small amount of methylenechloride, followed by solidification by the addition of diethyl ether,whereby the title compound (50 mg) was obtained as a pale yellow solid.

[6134]¹H-NMR (DMSO-d₆) δ: 2.33-3.75 (19H, m), 4.35-5.84 (4H, m),7.01-7.02 (3H, m), 7.31 (1H, d, J=8.8 Hz), 7.48 (1H, d, J=9.0 Hz), 7.76(1H, s), 12.41 (1H, s).

[6135] MS (FAB) m/z: 672 (M+H)⁺.

Example B-1554-[(5-Chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[6-[phenylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6136] In the same manner as in Example B-95, the title compound wasobtained.

[6137]¹H-NMR (DMSO-d₆) δ: 2.33-3.74 (19H, m), 4.34-5.71 (4H, m), 7.02(1H, s), 7.31 (1H, d, J=8.6 Hz), 7.47 (1H, d, J=9.0 Hz), 7.57-7.61 (2H,m), 7.65-7.67 (1H, m), 7.76 (1H, s), 7.80 (2H, d, J=7.8 Hz), 12.40 (1H,s).

[6138] HRMS (FAB) m/z: 733.1333 (M+H)⁺ (calcd for C₃₁H₃₃ClN₆O₇S₃,733.1340).

Example B-1565-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[[6-(tert-butoxycarbonyl)piperazine

[6139] In diethyl ether (8 ml) dried by a molecular sieve was dissolved6-(tert-butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(203 mg). After the container employed was purged with argon, thetemperature was cooled to −78° C. To the resulting solution, n-butyllithium (a 1.66 mole n-hexane solution, 506 μl) was added dropwise,followed by stirring at the same temperature for 1.5 hours. While acarbon dioxide gas was blown into the reaction mixture, the mixture wasstirred at the same temperature for 1 hour. After warming up to roomtemperature, the solvent was distilled off under reduced pressure,whereby crude lithium6-(tert-butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylatewas obtained. This product was provided for the subsequent reactionwithout purification. In N,N-dimethylformamide (4 ml) was dissolved3-(N-methylcarbamoyl)-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]piperazine(248 mg), followed by the addition of the crude lithium6-(tert-butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(ca. 550 μmol), which had been obtained above,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (144 mg) and1-hydroxybenzotriazole (34 mg). The resulting mixture was stirredovernight at room temperature. Methylene chloride was added to thereaction mixture. The resulting mixture was washed with a saturatedaqueous solution of sodium bicarbonate, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by flash column chromatography (hexane:ethylacetate=2:1) using as a carrier silica gel, whereby the title compound(121 mg) was obtained as a white solid.

[6140]¹H-NMR (CDCl₃) δ: 1.12-1.17 (3H, m), 1.49 (9H, s), 2.62-3.23 (7H,m), 3.63 (1H, d, J=12.3 Hz), 4.22 (1H, d, J=17.9 Hz), 4.55-4.74 (2H, m),4.83-4.89 (1H, m), 5.09-5.16 (1H, m), 5.25-6.49 (2H, m), 7.06 (1H, s),7.27-7.30 (2H, m), 7.38-7.42 (1H, m), 7.64 (1H, s), 10.62-10.67 (1H, m).

Example B-1574-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6141] In the same manner as in Example B-1, the title compound wasobtained.

[6142]¹H-NMR (DMSO-d₆) δ: 1.39-1.40 (3H, m), 2.32-3.68 (10H, m),4.21-5.00 (4H, m), 5.44-6.15 (1H, m), 7.01 (1H, s), 7.31 (1H, dd, J=8.5,2.0 Hz), 7.48 (1H, d, J=8.5 Hz), 7.77 (1H, s), 8.11-8.14 (1H, m),9.38-9.75 (2H, m), 12.42 (1H, s).

[6143] HRMS (FAB) m/z: 537.1140 (M+H)⁺ (calcd for C₂₂H₂₆N₆O₄ClS₂,537.1145).

Example B-1584-[(5-Chloroindol-2-yl)sulfonyl]-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-(N-methylcarbamoyl)piperazineHydrochloride

[6144] In a saturated solution of hydrochloride in ethanol (2 ml) wasdissolved1-[[6-(tert-butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine(40 mg), followed by stirring at room temperature for 1 hour. Diethylether was added to the reaction mixture. The precipitate so formed wascollected by filtration and washed with diethyl ether. Methylenechloride (7 ml) and triethylamine (81 μl) were added, followed by theaddition of acetic acid (34 μl). To the resulting mixture were added a30% aqueous solution (21 μl) of formaldehyde and sodiumtriacetoxyborohydride (64 mg), followed by stirring at room temperaturefor 30 minutes. The solvent was distilled off under reduced pressure.Methylene chloride was added and the resulting mixture was washed withwater and saturated aqueous NaCl solution. The organic layer was driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was dissolved in a 1N ethanolhydrochloride solution. After stirring at room temperature for 5minutes, the solvent was distilled off under reduced pressure. Theprecipitate so formed was collected by filtration and washed withdiethyl ether, whereby the title compound (68 mg) was obtained as awhite solid.

[6145]¹H-NMR (DMSO-d₆) δ: 1.32-1.40 (3H, m), 2.33-3.94 (13H, m),4.23-4.26 (1H, m), 4.44-5.01 (3H, m), 5.50-6.16 (1H, m), 7.02 (1H, s),7.31 (1H, dd, J=8.8, 2.0 Hz), 7.48 (1H, d, J=8.8 Hz), 7.77 (1H, s),8.10-8.16 (1H, m), 11.15-11.54 (1H, m), 12.43 (1H, s).

Example B-1594-[(6-Chloronaphthalen-2-yl)sulfonyl]-2(N-methylcarbamoyl)-1-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineTrifluoroacetate

[6146] To a solution of6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine(120 mg) in tetrahydrofuran (4.0 ml) were added water (1.0 ml) andlithium hydroxide (18.0 mg) at room temperature.

[6147] After stirring for 10 minutes, the solvent was distilled offunder reduced pressure. To a solution of the residue inN,N-dimethylformamide were added1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-(N-methylcarbamoyl)piperazinehydrochloride (190 mg), 1-hyroxybenzotriazole monohydrate (11.5 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (90.0 mg) at roomtemperature. After stirring for 4 hours, methylene chloride (30 ml) andwater (250 ml) were added to the reaction mixture to separate it intolayers. The water layer was extracted with methylene chloride (20 ml).The organic layers were combined, washed with a saturated aqueoussolution (50 ml) of sodium bicarbonate, dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by chromatography on a silica gel column (silicagel: 25 g, methylene chloride:acetone=5:1→3:1), whereby a colorlesstransparent oil was obtained. To a solution of the resulting substancein methylene chloride (4.0 ml) was added trifluoroacetic acid (4.0 ml)at room temperature and the resulting mixture was stirred for 1 hour.The reaction mixture was concentrated under reduced pressure. Theresidue was reprecipitated from a methylene chloride—methanol—diethylether system, whereby the title compound (165 mg) was obtained as a palebrown solid.

[6148]¹H-NMR (DMSO-d₆) δ: 2.30-2.70 (2H, m), 2.58 (3H, d, J=3.9 Hz),2.77 (2H, br d, J=16.1 Hz), 3.05-3.60 (3H, m), 3.71 (1H, br d, J=11.2Hz), 4.29 (1H, br d, J=11.7 Hz), 4.35-4.50 (2H+½ of 1H, m), 4.96 (½ of1H, br s), 5.05 (½ of 1H, br d, J=13.2 Hz), 5.78 (½ of 1H, br s), 7.71(1H, d, J=8.3 Hz), 7.73-7.83 (1H, m), 8.00-8.20 (1H, m), 8.15 (1H, d,J=8.3 Hz), 8.24 (1H, s), 8.25 (1H, d, J=8.3 Hz), 8.48 (½ of 1H, s), 8.49(½ of 1H, s), 9.34 (2H, br s).

[6149] MS (FAB) m/z: 518 (M+H)⁺.

Example B-1604-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6150] In the same manner as in Example B-32, the title compound wasobtained.

[6151]¹H-NMR (DMSO-d₆) δ: 2.48 (3H, s), 2.52-2.80 (6H, m), 2.80-3.00(3H, m), 3.10 (½ of 1H, t, J=11.2 Hz), 3.49 (½ of 1H, t, J=11.2 Hz),3.54 (2H, s), 3.78 (½ of 1H, br d, J=10.3 Hz), 3.86 (½ of 1H, br d,J=11.2 Hz), 4.45 (1H, t, J=11.4 Hz), 4.63 (½ of 1H, br d, J=12.7 Hz),5.24 (½ of 1H, s), 5.38 (½ of 1H, br d, J=12.7 Hz), 6.12 (½ of 1H, brs), 6.16 (½ of 1H, s), 6.40 (½ of 1H, br s), 7.58 (1H, d, J=7.8 Hz),7.80 (1H, d, J=7.8 Hz), 7.86-7.96 (3H, m), 8.34 (1H, s).

[6152] MS (FAB) m/z: 532 (M+H)⁺.

Example B-1611-[[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[6153] In the same manner as in Example B-62, the title compound wasobtained.

[6154]¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.64 (2H, br s), 3.22 (4H, br s),3.71 (2H, br s), 3.90 (2H, br s), 4.42 (2H, br s), 4.53 (2H, br s), 6.97(1H, d, J=2.0 Hz), 7.33 (1H, dd, J=8.8, 2.0 Hz), 7.37 (1H, d, J=8.8 Hz),7.67 (1H, s), 8.71 (1H, br s).

Example B-1621-[[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine

[6155] In the same manner as in Example B-62, the title compound wasobtained.

[6156]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.50-2.70 (2H, m), 2.70-3.20 (2H+½of 1H, m), 3.38 (½ of 1H, t, J=11.2 Hz), 3.50-3.95 (11H+½ of 1H, m),3.99 (½ of 1H, br d, J=12.7 Hz), 4.40-4.60 (½ of 1H, br), 4.53 (2H, s),4.64 (½ of 1H, br d, J=13.7 Hz), 5.02 (½ of 11H, br s), 5.24 (½ of 1H,br s), 5.79 (½ of 1H, br s), 7.00 (1H, s), 7.20-7.35 (1H, m), 7.38 (1H,d, J=8.8 Hz), 7.65 (½ of 1H, s), 7.67 (½ of 1H, s), 9.89 (½ of 1H, brs), 10.60-11.00 (½ of 1H, br).

Example B-1631-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6157] To a solution of1-[[6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine(100 mg) in methylene chloride (3.0 ml) was added trifluoroacetic acid(3.0 ml) at room temperature, followed by stirring for 15 minutes. Thereaction mixture was concentrated under reduced pressure. To the residuewere added methylene chloride (4.0 ml), triethylamine (50.0 μl), aceticacid (21.0 μl), formalin (23.5 μl) and sodium triacetoxyborohydride(58.0 mg) at room temperature. After stirring for 1 hour, methylenechloride (20 ml) and a saturated aqueous solution (50 ml) of sodiumbicarbonate were added to the reaction mixture to separate it intolayers. The water layer was extracted with methylene chloride (20 ml).The organic layers were combined, dried over anhydrous sodium sulfateand distilled under reduced pressure to remove the solvent. The residuewas purified by preparative thin-layer chromatography(chloroform:methanol=10:1) using silica gel, whereby the free form (82.6mg) of the title compound was obtained as a colorless solid. To theresulting compound were added a 1N aqueous solution of hydrochloricacid, tetrahydrofuran and methanol, followed by concentration underreduced pressure, whereby the title compound was obtained as a colorlesssolid.

[6158]¹H-NMR (DMSO-d₆) δ: 2.90 (4H, s), 3.11 (3H, br s), 3.25-3.75 (2H,br), 3.35 (2H, s), 3.75 (2H, br s), 4.16 (2H, br s), 4.20-4.75 (2H, br),7.04 (1H, s), 7.32 (1H, dd, J=8.8, 1.0 Hz), 7.50 (1H, d, J=8.8 Hz), 7.78(1H, d, J=1.0 Hz), 11.51 (1H, br s), 12.46 (1H, s)

[6159] MS (FAB) m/z: 464 (M+H)⁺.

Example B-1644-(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazineHydrochloride

[6160] In the same manner as in Example B-163, the title compound wasobtained.

[6161]¹H-NMR (DMSO-d₆) δ: 2.30-2.75 (2H, m), 2.75-3.20 (2H, m), 2.90(3H, s), 3.20-3.90 (15H, m), 4.30-4.45 (1H+½ of 1H, m), 4.55-4.70 (1H,m), 4.89 (½ of 1H, br s), 5.05 (½ of 1H, br s), 5.47 (½ of 1H, br s),7.04 (1H, s), 7.29-7.35 (1H, m), 7.50 (1H, dd, J=8.8, 2.9 Hz), 7.76-7.80(1H, m), 11.45-11.95 (1H, br), 12.49 (1H, br s).

[6162] MS (FAB) m/z: 591 (M+H)⁺.

Example B-1651-[[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine

[6163] To a solution of lithium6-(tert-butoxycarbonyl)4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(70.0 mg) in N,N-dimethylformamide (4.0 ml) were added1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine hydrochloride (90.0mg), 1-hydroxybenzotriazole monohydrate (7.0 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (64.0 mg) at roomtemperature. After stirring for 2 days, ethyl acetate (30 ml) and water(500 ml) were added to the reaction mixture to separate it into layers.The water layer was extracted with ethyl acetate (30 ml). The organiclayers were combined, washed with a saturated aqueous solution of sodiumbicarbonate (100 ml), dried over anhydrous sodium sulfate and distilledunder reduced pressure to remove the solvent. The residue was purifiedby preparative thin-layer chromatography (hexane:ethyl acetate=1:1)using silica gel, whereby the title compound (37.9 mg) was obtained as acolorless transparent glassy substance.

[6164]¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.65 (2H, s), 3.27 (4H, t, J=5.0Hz), 3.70 (2H, s), 3.91 (2H, s), 4.42 (2H, s), 4.53 (2H, s), 7.45 (1H,dd, J=8.8, 1.5 Hz), 7.77 (1H, s), 7.81 (1H, d, J=8.8 Hz), 7.86 (1H, d,J=1.5 Hz).

[6165] MS (FAB) m/z: 567 (M+H)⁺.

Example B-1661-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6166] In the same manner as in Example B-163, the title compound wasobtained.

[6167]¹H-NMR (DMSO-d₆) δ: 2.90 (3H, s), 2.94 (1H, br s), 3.10-3.25 (4H,m), 3.49 (2H, s), 3.64 (1H, br s), 3.79 (2H, s), 4.21 (2H, s), 4.39 (1H,br s), 4.60 (1H, br s), 7.58 (1H, dd, J=8.8, 2.0 Hz), 8.07 (1H, d, J=8.8Hz), 8.10 (1H, s), 8.34 (1H, d, J=2.0 Hz), 11.70 (1H, br s).

[6168] MS (FAB) m/z: 481 (M+H)⁺.

Example B-1671-[(6-Methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl)sulfonyl]piperazine

[6169] In the same manner as in Example B-103, the title compound wasobtained.

[6170]¹H-NMR (CDCl₃) δ: 0.25 (9H, s), 2.51 (3H, s), 2.69 (2H, t, J=5.4Hz), 2.78 (2H, t, J=5.4 Hz), 3.52 (2H, br s), 3.55 (2H, br s), 3.59 (2H,s), 3.89 (2H, br s), 4.41 (2H, br s), 7.42 (2H, t, J=7.6 Hz), 7.47 (1H,s), 7.55 (1H, t, J=7.6 Hz), 7.59 (1H, dd, J=8.8, 1.7 Hz), 7.69 (1H, d,J=1.7 Hz), 8.00 (2H, d, J=7.6 Hz), 8.22 (1H, d, J=8.8 Hz).

Example B-1681-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6171] In the same manner as in Example B-104, the title compound wasobtained.

[6172]¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 2.66 (2H, t, J=5.4 Hz), 2.75 (2H,t, J=5.4 Hz), 3.04 (1H, s), 3.21 (4H, t, J=4.4 Hz), 3.54 (2H, s), 3.89(2H, br s), 4.43 (2H, br s), 7.00 (1H, s), 7.37 (1H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 1.5 Hz), 7.86 (1H, br s), 8.85 (1H, br s).

[6173] MS (FAB/glycerol) m/z: 454 (M+H)⁺.

Example B-1691-[[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-ethylpiperazine

[6174] In the same manner as in Example B-165, the title compound wasobtained.

[6175]¹H-NMR (CDCl₃) δ: 0.90 (½ of 3H, t, J=7.1 Hz), 0.96 (½ of 3H, t,J=7.1 Hz), 1.47 (9H, s), 1.78-2.03 (2H, m), 2.45-2.73 (4H, m), 3.18 (½of 1H, t, J=11.5 Hz), 3.51 (½ of 1H, t, J=11.5 Hz), 3.60-3.92 (4H, m),4.52 (2H, s), 4.62 (½ of 1H, d, J=13.0 Hz), 4.79 (½ of 1H, br s), 5.20(½ of 1H, br s), 5.40 (½ of 1H, br s), 6.94 (1H, d, J=1.5 Hz), 7.31 (1H,dd, J=8.8, 2.0 Hz), 7.37 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=2.0 Hz), 8.87(1H, br s).

[6176] MS (FAB) m/z: 578 (M+H)⁺.

Example B-1704-[(5-Chloroindol-2-yl)sulfonyl]-2-ethyl]-[(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineTrifluoroacetate

[6177] To a solution of1-[[6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-ethylpiperazine(320 mg) in methylene chloride (5.0 ml) was added trifluoroacetic acid(5.0 ml) at room temperature, followed by stirring for 10 minutes. Thereaction mixture was concentrated under reduced pressure, whereby thetitle compound (423 mg) was obtained as a pale brown solid.

[6178]¹H-NMR (DMSO-d₆) δ: 0.78 (½ of 3H, t, J=6.9 Hz), 0.83 (½ of 3H, t,J=6.9 Hz), 1.47 (9H, s), 1.65-1.95 (2H, m), 2.30-2.70 (2H, m), 2.80 (2H,s), 3.13 (½ of 1H, t, J=12.7 Hz), 3.37-4.00 (2H+½ of 1H, m), 3.42 (2H,s), 4.30-4.47 (2H+½ of 1H, m), 4.60 (½ of 1H, br s), 4.73 (½ of 1H, d,J=14.0 Hz), 4.91 (½ of 1H, br s), 8.01 (1H, s), 7.30 (1H, d, J=8.8 Hz),7.47 (1H, d, J=8.8 Hz), 7.76 (1H, s), 9.36 (2H, br s), 12.42 (1H, s).

[6179] MS (FAB) m/z: 478 (M+H)⁺.

Example B-1714-[(5-Chloroindol-2-yl)sulfonyl]-2-ethyl-1-[(6-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6180] In the same manner as in Example B-32, the title compound wasobtained.

[6181]¹H-NMR (DMSO-d₆) δ: 0.73-0.83 (3H, m), 1.60-1.92 (2H, m),2.30-2.70 (2H, m), 2.75-3.03 (2H, m), 2.89 (3H, s), 3.03-3.53 (2H+½ of1H, m), 3.53-3.80 (2H+½ of 1H, m), 4.20-4.45 (1H+½ of 1H, br), 4.60(1H+½ of 1H, br s), 4.76 (½ of 1H, d, J=13.0 Hz), 4.92 (½ of 1H, br s),7.00 (1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.47 (1H, d, J=8.8 Hz), 7.75(1H, d, J=2.0 Hz), 11.57 (1H, br s), 12.43 (1H, s).

[6182] MS (FAB) m/z: 492 (M+H)⁺.

Example B-1721-[[6-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[6183] In the same manner as in Example B-159, the title compound wasobtained.

[6184]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.96 (2H, t, J=5.9 Hz), 3.14 (2H,t, J=5.0 Hz), 3.27 (2H, t, J=5.1 Hz), 3.53 (2H, t, J=5.0 Hz), 3.75 (2H,t, J=5.9 Hz), 3.93 (2H, t, J=5.1 Hz), 4.62 (2H, s), 6.96 (1H, s), 7.35(1H, dd, J=8.5, 1.7 Hz), 7.38 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=1.7 Hz),8.48 (1H, s), 8.77 (1H, br s).

[6185] MS (FAB) m/z: 561 (M+H)⁺.

Example B-1731-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]carbonyl]piperazineTrifluoroacetate

[6186] In the same manner as in Example B-170, the title compound wasobtained.

[6187]¹H-NMR (DMSO-d₆) δ: 2.96 (2H, t, J=4.5 Hz), 3.03 (2H, t, J=6.0Hz), 3.11 (2H, t, J=4.5 Hz), 3.29 (2H, t, J=4.5 Hz), 3.49 (2H, br s),3.75 (2H, t, J=4.5 Hz), 4.36 (2H, s), 7.03 (1H, s), 7.32 (1H, dd, J=8.8,1.7 Hz), 7.49 (1H, d, J=8.8 Hz), 7.78 (1H, d, J=1.7 Hz), 8.70 (1H, s),9.25 (2H, br s), 12.46 (1H, s).

[6188] MS (FAB) m/z: 461 (M+H)⁺.

Example B-1741-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[6189] In the same manner as in Example B-32, the title compound wasobtained.

[6190]¹H-NMR (DMSO-d₆) δ: 2.92 (3H, s), 2.98 (2H, br s), 3.06 (1H, brs), 3.13 (2H, t, J=5.0 Hz), 3.28 (1H, br s), 3.32 (2H, t, J=5.0 Hz),3.46 (1H, br s), 3.70 (1H, br s), 3.77 (2H, br s), 4.34 (1H, br d,J=15.4 Hz), 4.57 (1H, br d, J=15.4 Hz), 7.04 (1H, d, J=1.6 Hz), 7.34(1H, dd, J=8.8, 2.0 Hz), 7.62 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz),8.71 (1H, s), 11.67 (1H, br s), 12.50 (1H, d, J=1.6 Hz).

[6191] MS (FAB) m/z: 475 (M+H)⁺.

Example B-1751-[[6-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)piperazine

[6192] In the same manner as in Example B-159, the title compound wasobtained.

[6193]¹H-NMR (CDCl₃) δ: 1.49 (½ of 9H, s), 1.50 (½ of 9H, s), 2.60-2.72(½ of 1H, m), 2.85-3.12 (6H, m), 3.12-3.30 (1H, m), 3.45-3.70 (1H, m),3.70-3.90 (2H+½ of 1H, m), 4.32 (½ of 1H, br s), 4.60-4.75 (½ of 1H+2H,m), 4.81 (½ of 1H, d, J=12.9 Hz), 5.31-5.35 (½ of 1H, m), 6.68 (½ of 1H,br s), 7.04 (½ of 1H, s), 7.07 (½ of 1H, s), 7.20-7.35 (1H, m), 7.39 (½of 1H, d, J=8.8 Hz), 7.40 (½ of 1H, d, J=8.3 Hz), 7.62 (½ of 1H, s),7.66 (½ of 1H, s), 7.87 (½ of 1H, br s), 10.47 (½ of 1H, br s), 10.70 (½of 1H, br s).

[6194] MS (FAB) m/z: 618 (M+H)⁺.

Example B-1764-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]carbonyl]piperazineTrifluoroacetate

[6195] In the same manner as in Example B-170, the title compound wasobtained.

[6196]¹H-NMR (DMSO-d₆) δ: 2.30-2.58 (2H, m), 2.60 (½ of 3H, d, J=4.4Hz), 2.64 (½ of 3H, d, J=4.2 Hz), 2.65-2.75 (1H, m), 3.00 (½ of 2H, t,J=5.4 Hz), 3.06 (½ of 2H, t, J=6.2 Hz), 3.29 (½ of 1H, br t, J=11.0 Hz),3.39 (½ of 1H, br d, J=13.5 Hz), 3.50 (2H, br s), 3.53-3.80 (½ of 1H+1H,m), 4.10-4.30 (½ of 1H, m), 4.35 (½ of 2H, s), 4.38 (½ of 2H, s), 4.50(½ of 1H, br d, J=13.5 Hz), 5.05 (½ of 1H, br s), 7.00 (½ of 1H, s),7.01 (½ of 1H, s), 7.28-7.38 (1H, m), 7.48 (½ of 1H, d, J=8.8 Hz), 7.49(½ of 1H, d, J=8.8 Hz), 7.77 (½ of 1H, d, J=1.7 Hz), 7.78 (½ of 1H, d,J=1.7 Hz), 7.90-8.03 (½ of 1H, m), 8.07-8.17 (½ of 1H, m), 8.69 (½ of1H, s), 8.73 (½ of 1H, s), 9.24 (2H, br s), 12.43 (1H, s).

[6197] MS (FAB) m/z: 518 (M+H)⁺.

Example B-1774-[(5-Chloroindol-2-yl)sulfonyl]-2-(N-methylcarbamoyl)-1-[(6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl]carbonyl]piperazineHydrochloride

[6198] In the same manner as in Example B-32, the title compound wasobtained.

[6199]¹H-NMR (DMSO-d₆) δ: 2.30-2.55 (2H, m), 2.61 (½ of 3H, d, J=3.5Hz), 2.65 (½ of 3H, d, J=4.2 Hz), 2.68-2.77 (1H, m), 2.93 (3H, br s),2.97-3.18 (1H, m), 3.20-3.80 (6H, m) 4.04-4.65 (3H, m), 5.07 (½ of 1H,br s), 7.00 (½ of 1H, d, J=1.5 Hz), 7.02 (½ of 1H, d, J=1.7 Hz),7.30-7.37 (1H, m), 7.50 (½ of 1H, d, J=8.8 Hz), 7.51 (½ of 1H, d, J=8.8Hz), 7.78 (½ of 1H, d, J=1.7 Hz), 7.80 (½ of 1H, d, J=2.0 Hz), 8.05 (½of 1H, br s), 8.15 (½ of 1H, br d, J=4.2 Hz), 8.70 (½ of 1H, s), 8.74 (½of 1H, s), 11.68 (1H, br s), 12.48 (1H, s).

[6200] MS (FAB) m/z: 532 (M+H)⁺.

Example B-1784-(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[2-(piperidin-1-yl)ethyl]piperazineHydrochloride

[6201] In the same manner as in Example B-62, the title compound wasobtained.

[6202]¹H-NMR (DMSO-d₆) δ: 1.16-3.79 (26H, m), 4.37-4.45 (1H, m),4.68-4.75 (2H, m), 5.40-5.47 (1H, m), 7.02 (1H, d, J=5.1 Hz), 7.32 (1H,dd, J=2.2, 8.8 Hz), 7.49 (1H, d, J=8.8 Hz), 7.77 (1H, s).

[6203] MS (FAB) m/z: 591 [(M+H)⁺, Cl³⁵], 593 [(M+H)⁺, Cl³⁷].

Example B-1794-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-[N-(2-methoxyethyl)amino]ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6204] In the same manner as in Example B-62, the title compound wasobtained.

[6205]¹H-NMR (DMSO-d₆) δ: 2.33-4.77 (21H, m), 3.29 (3H, s), 3.34 (3H,s), 5.39-5.43 (1H, m), 7.01 (1H, d, J=4.4 Hz), 7.30 (1H, dd, J=7.8, 2.0Hz), 7.49 (1H, d, J=8.8 Hz), 7.76 (1H, s).

[6206] MS (FAB) m/z: 581 [(M+H)⁺, Cl³⁵], 583 [(M+H)⁺, Cl³⁷].

Example B-1801-[[6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[2-(piperidin-1-yl)ethyl]piperazine

[6207] In the same manner as in Example B-62, the title compound wasobtained.

[6208]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.16-3.79 (23H, m), 4.45-4.59 (1H,m), 4.65-4.75 (2H, m), 6.70-6.80 (1H, m), 6.96 (1H, s), 7.28-7.31 (1H,m), 7.64 (1H, d, J=1.7 Hz), 8.02 (1H, s).

[6209] MS (FAB) m/z: 677 (M+H)⁺.

Example B-1814-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[2-(piperidin-1-yl)ethyl]piperazine

[6210] In the same manner as in Example B-95, the title compound wasobtained.

[6211]¹H-NMR (CDCl₃) δ: 1.54-3.83 (23H, m), 2.89 (3H, s), 4.59 (2H, s),4.55-4.84 (1H, m), 5.61-5.84 (1H, m), 7.00 (1H, d, J=15.0 Hz), 7.27-7.29(1H, m), 7.50-7.57 (1H, m), 7.63 (1H, s).

[6212] MS (FAB) m/z: 655 [(M+H)⁺, Cl³⁵], 657 [(M+H)⁺, Cl³⁷].

Example B-1824-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[3-(thien-2-yl)propyl]piperazineHydrochloride

[6213] In N,N-dimethylformamide (15 ml) were dissolved1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[3-(thien-2-yl)propyl]piperazine(257 mg), lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (129mg), 1-(3-dimethylaminopropyl)-3-ethylarbodiimide hydrochloride (131 mg)and 1-hydroxybenzotriazole hydrate (76.4 mg). Under ice cooling,diisoproylethylamine (180 μl) was added dropwise to the resultingsolution, followed by stirring at room temperature for 15.5 hours. Thereaction mixture was extracted with methylene chloride and water. Theorganic layer was washed with saturated aqueous NaCl solution, driedover anhydrous sodium sulfate and distilled under reduced pressure toremove the solvent. The residue was subjected to column chromatography(2% methanol—methylene chloride) using as a carrier silica gel. Afterconversion into the corresponding hydrochloride by the addition of 1Naqueous hydrochloric acid in ethanol, methylene chloride methanol—etherwas added to solidify the hydrochloride. The resulting solid waspurified again by subjecting it to thin-layer chromatography (10%methanol—methylene chloride), followed by the addition of 1N aqueoushydrochloric acid in ethanol to form the corresponding hydrochloride.Methylene chloride—methanol—ether was added to solidify thehydrochloride. The resulting solid was collected by filtration, washedwith ether and then dried, whereby the title compound (62.6 mg) wasobtained as colorless powder.

[6214]¹H-NMR (DMSO-d₆) δ: 1.45-2.00 (4H, m), 2.30-3.80 (11H, m),4.30-4.80 (3H, m), 5.15-5.65 (1H, m), 6.75-6.85 (1H, m), 6.85-6.95 (1H,m), 7.01 (1H, s), 7.20-7.35 (2H, m), 7.48 (1H, d, J=9.0 Hz), 7.75 (1H,s), 11.42 (1H, br), 12.44 (1H, s).

[6215] MS (FAB) m/z: 604 [(M+H)⁺, Cl³⁵], 606 [(M+H)⁺, Cl³⁷].

Example B-1834-[(5-Chloroindol-2-yl)sulfonyl]-2-[3-(3,4-dimethoxyphenyl)propyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6216] In the same manner as in Example B-182, the title compound wasobtained.

[6217]¹H-NMR (DMSO-d₆) δ: 1.40-1.90 (4H, m), 2.40-2.70 (1H, m), 2.90(3H, s), 3.00-3.20 (2H, m), 3.30-3.80 (16H, m), 4.30-4.80 (3H, m),5.20-5.60 (1H, m), 6.60-6.70 (1H, m), 6.82 (1H, d, J=8.1 Hz), 7.01 (1H,s), 7.25-7.35 (1H, m), 7.48 (1H, d, J=8.8 Hz), 7.70-7.80 (1H, m),11.20-11.50 (1H, br), 12.43 (1H, s).

[6218] MS (FAB) m/z: 658 [(M+H)⁺, Cl³⁵], 660 [(M+H)⁺, Cl³⁷].

Example B-1844-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[2-[(pyrrolidin-1-yl)sulfonyl]ethyl]piperazineHydrochloride

[6219] In the same manner as in Example B-182, the title compound wasobtained.

[6220]¹H-NMR (DMSO-d₆) δ: 1.80-1.90 (4H, m), 2.10-2.30 (2H, m),2.40-3.85 (15H, m), 2.90 (3H, s), 4.30-4.90 (3H, m), 5.30-5.50 (1H, m),7.02 (1H, s), 7.25-7.35 (1H, m), 7.48 (1H, d, J=8.8 Hz), 7.76 (1H, s),11.27 (1H, br), 12.44 (1H, s).

[6221] MS (FAB) m/z: 641 [(M+H)⁺, Cl³⁵], 642 [(M+H)⁺, Cl³⁷].

Example B-1851-[[6-Methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl]carbonyl]-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl)sulfonyl]piperazine

[6222] In the same manner as in Example B-103, the title compound wasobtained.

[6223]¹H-NMR (CDCl₃) δ: 0.25-0.35 (9H, m), 2.45-2.55 (3H, m), 2.55-2.65(2H, m), 2.65-2.75 (2H, m), 3.45-3.55 (6H, m), 3.85-3.95 (4H, m),7.40-7.65 (6H, m), 7.70-7.75 (1H, m), 8.00-8.05 (2H, m), 8.20-8.25 (1H,m).

[6224] MS (FAB) m/z: 665 (M+H)⁺.

Example B-1861-[(5-Ethynylindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)carbonyl]piperazine

[6225] In the same manner as in Example B-104, the title compound wasobtained.

[6226]¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 2.50-2.60 (2H, m), 2.65 (2H, t,J=5.6 Hz), 3.17 (4H, t, J=5.0 Hz), 3.46 (2H, s), 3.90 (4H, br s), 6.84(1H, s), 7.00 (1H, d, J=1.0 Hz), 7.35-7.40 (1H, m), 7.45-7.50 (1H, m),7.87 (1H, s), 8.92 (1H, br s).

[6227] MS (FAB) m/z: 453 (M+H)⁺.

Example B-1871-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6228] In the same manner as in Example B-62, the title compound wasobtained.

[6229]¹H-NMR (DMSO-d₆) δ: 2.76 (2H, br), 2.89 (3H, s), 3.05-3.10 (2H,m), 3.35-3.50 (2H, m), 3.74 (4H, br), 4.10-4.60 (2H, m), 6.97 (1H, s),7.00-7.05 (1H, m), 7.30-7.35 (1H, m), 7.49 (1H, d, J=9.0 Hz), 7.78 (1H,d, J=2.0 Hz), 10.88 (1H, br s), 12.45 (1H, s).

[6230] MS (FAB) m/z: 463 [(M+H)⁺, Cl³⁵], 465 [(M+H)⁺, Cl³⁷].

Example B-1881-[(2-tert-Butoxycarbonylisoindolin-5-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[6231] In the same manner as in Example B-62, the title compound wasobtained.

[6232]¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 3.13 (4H, br s), 3.72 (4H, br s),4.60-4.70 (4H, m), 6.96 (1H, s), 7.18-7.30 (3H, m), 7.31-7.40 (2H, m),7.69 (1H, s), 8.93 (1H, s).

[6233] MS (FAB) m/z: 545 [(M+H)⁺, Cl³⁵], 547 [(M+H)⁺, Cl³⁷].

[6234] Elementary analysis for C₂₆H₂₉ClN₄O₅S.H₂O

[6235] Calculated: C, 55.46; H, 5.55; N, 9.95.

[6236] Found: C, 55.69; H, 5.35; N, 9.85.

Example B-1891-[(5-Chloroindol-2-yl)sulfonyl]-4-[(isoindolin-5-yl)carbonyl]piperazine

[6237] In the same manner as in Example B-1, the title compound wasobtained.

[6238] m.p. 196-199° C. (dec).

[6239]¹H-NMR (DMSO-d₆) δ: 3.08 (4H, br s), 3.44 (2H, br s), 3.69 (2H, brs), 4.47 (2H, s), 4.50 (2H, s), 7.02 (1H, s), 7.30-7.45 (4H, m), 7.51(1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.0 Hz), 9.65 (2H, br s), 12.44 (1H,s).

[6240] MS (FAB) m/z: 445 [(M+H)⁺, Cl³⁵], 447 [(M+H)⁺, Cl³⁷].

[6241] Elementary analysis for C₂₁H₂₁ClN₄O₃S

[6242] Calculated: C, 48.75; H, 5.06; Cl, 13.70; N, 10.83; S, 6.20.

[6243] Found: C, 49.06; H, 4.96; Cl, 13.61; N, 10.63; S, 6.08.

Example B-1901-[(5-Chloroindol-2-yl)sulfonyl]-4-[(2-methylisoindolin-5-yl)carbonyl]piperazine

[6244] In the same manner as in Example B-32, the title compound wasobtained.

[6245] m.p. 175-180° C. (dec).

[6246]¹H-NMR (DMSO-d₆) δ: 2.97 (3H, br s), 3.09 (4H, br s), 3.43 (2H, brs), 3.68 (2H, br s), 4.57 (4H, br s), 7.02 (1H, s), 7.30-7.45 (4H, m),7.51 (1H, d, J=9.0 Hz), 7.79 (1H, s), 11.58 (1H, br s), 12.46 (1H, s).

[6247] MS (FAB) m/z: 459 [(M+H)⁺, Cl³⁵], 461 [(M+H)⁺, Cl³⁷].

[6248] Elementary analysis for C₂₂H₂₃ClN₄O₃S.0.95HCl.1.6H₂O

[6249] Calculated: C, 50.58; H, 5.24; Cl, 13.23; N, 10.72; S, 6.14.

[6250] Found C, 50.90; H, 5.46; Cl, 13.10; N, 10.32; S, 5.97.

Example B-1911-[(5-Chloroindol-2-yl)sulfonyl]-3-[N-(2-hydroxyethyl)carbamoylmethyl-4-(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonylpiperazineHydrochloride

[6251] In the same manner as in Example B-62, the title compound wasobtained.

[6252]¹H-NMR (DMSO-d₆) δ: 2.30-3.82 (20H, m), 2.90 (3H, s), 4.30-4.50(2H, m), 4.50-4.75 (1.5H, m), 5.00-5.10 (0.5H, m), 5.28-5.38 (0.5H, m),5.80-5.90 (0.5H, m), 7.02 (1H, s), 7.31 (1H, d, J=8.8 Hz), 7.48 (1H, d,J=8.8 Hz), 7.76 (1H, s), 7.95-8.05 (1H, m), 11.24 (0.5H, m), 11.39(0.5H, m), 12.43 (1H, s).

[6253] FAB-MS m/z: 580 [(M+H)⁺−H, Cl³⁵], 582 [(M+H)⁺−H, Cl³⁷].

Example B-1924-[(5-Chloroindol-2-yl)sulfonyl]-2-[2-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6254] In the same manner as in Example B-62, the title compound wasobtained.

[6255]¹H-NMR (DMSO-d₆) δ: 1.79-3.73 (22H, m), 2.89 (3H, s), 3.93 (4H,s), 4.43-4.75 (2H, m), 5.55 (1H, m), 7.01 (1H, d, J=6.1 Hz), 7.30 (1H,dd, J=1.9, 8.8 Hz), 7.49 (1H, d, J=8.8 Hz), 7.76 (1H, s), 12.45 (1H, s).

[6256] MS (FAB) m/z: 649 [(M+H)⁺, Cl³⁵], 651 [(M+H)⁺, Cl³⁷].

Example B-1934-[(5-Chloroindol-2-yl)sulfonyl]-2-[(1,3-dioxolan-2-yl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6257] In the same manner as in Example B-62, the title compound wasobtained.

[6258]¹H-NMR (CDCl₃) δ: 1.77 (2H, m), 2.22 (2H, m), 2.49-3.95 (15H, m),4.55-5.03 (3H, m), 5.66 (1H, m), 6.94 (1H, s), 7.28-7.37 (2H, m), 7.64(1H, d, J=1.7 Hz), 9.34 (1H, s).

[6259] MS (FAB) m/z: 566 [(M+H)⁺, Cl³⁵], 568 [(M+H)⁺, Cl³⁷].

Example B-1944-[(5-Chloroindol-2-yl)sulfonyl]-2-[(2-1,3-dioxoisoindol-2-yl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6260] In the same manner as in Example B-62, the title compound wasobtained.

[6261]¹H-NMR (CDCl₃) δ: 2.42-2.45 (3H, m), 2.55-2.84 (5.5H, m),3.31-3.57 (2H, m), 3.70-3.92 (4.5H, m), 4.42-4.51 (1H, m), 4.61 (⅔H,broad d, J=12.7 Hz), 5.25 (⅓H, broad), 5.82 (⅓H, broad), 6.22 (⅔H, broadd, J=9.7 Hz), 6.99 (1H, s), 7.30-7.38 (2H, m), 7.62-7.73 (5H, m), 7.79(⅔H, m), 8.97 (⅓H, broad).

[6262] MS (FAB) m/z: 639 (M+H)⁺.

Example B-1954-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[2-(2-naphthoxy)ethyl]piperazine

[6263] In the same manner as in Example B-62, the title compound wasobtained.

[6264]¹H-NMR (CDCl₃) δ: 2.28-2.51 (5H, m), 2.55-2.60 (2H, m), 2.78-2.87(4H, m), 3.26-3.29 (1H, m), 3.52-3.63 (2H, m), 3.84-3.87 (2H, m),4.06-4.19 (2H, m), 4.61 (⅔H, broad d, J=12.7 Hz), 5.16 (⅓H, broad), 5.71(⅓H, broad m), 6.22 (⅔H, broad), 6.87-6.94 (2H, m), 7.09 (1H, broad),7.22-7.33 (3H, m), 7.39-7.43 (1H, m), 7.64-7.74 (4H, m), 9.09 (1H, broads).

[6265] MS (FAB) m/z: 650 (M+H)⁺.

Example B-1964-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-(2-phenoxyethyl)piperazine

[6266] In the same manner as in Example B-62, the title compound wasobtained.

[6267]¹H-NMR (CDCl₃) δ: 2.26-2.40 (2H, m), 2.47 (3H, s), 2.55-2.61 (1H,m), 2.67-2.85 (5H, m), 3.24-3.30 (⅓H, m), 3.48-3.51 (⅔H, m), 3.62-3.65(2H, m), 3.82-4.08 (4H, m), 4.61 (⅔H, broad d, J=13.9 Hz), 5.12 (⅓H,broad), 5.82 (⅓H, broad d, J=12.9 Hz), 6.18 (⅔H, broad), 6.68-6.70 (1H,m), 6.87-6.92 (2H, m), 6.95 (1H, s), 7.21-7.23 (2H, m), 7.29-7.35 (2H,m), 7.65 (1H, s), 8.02 (⅓H, s), 9.03 (⅔H, broad s).

[6268] MS (FAB) m/z: 599 (M⁺, Cl³⁵), 601 (M⁺, Cl³⁷)

Example B-1974-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-hydroxyethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6269] In the same manner as in Example B-62, the title compound wasobtained.

[6270]¹H-NMR (CDCl₃) δ: 1.88-1.94 (2H, m), 2.48 (3H, s), 2.41-2.62 (2H,m), 2.75-2.90 (4H, m), 3.12-3.21 (1H, m), 3.33-3.85 (6H, m), 4.66 (⅔H,broad d, J=13.7 Hz), 4.88-4.90 (⅓H, m), 5.37-5.40 (⅔H, m), 6.18 (⅓H,broad d, J=13.4 Hz), 6.91-6.95 (1H, m), 7.29-7.37 (2H, m), 7.65 (1H, s),9.02 (1H, broad s).

[6271] MS (FAB) m/z: 524 [(M+H)⁺, Cl³⁵], 526 [(M+H)⁺, Cl³⁷].

Example B-1984-(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[2-(2-oxo-1,3-oxazolan-3-ylyl)ethyl]piperazine

[6272] In the same manner as in Example B-62, the title compound wasobtained.

[6273]¹H-NMR (CDCl₃) δ: 1.90 (1H, broad), 2.23-2.32 (1H, broad m), 2.48(3H, s), 2.65 (2H, broad m), 2.80 (2H, broad s), 2.87-2.89 (2H, broadm), 3.21-3.45 (3H, broad m), 3.56 (2H, broad m), 3.67 (2H, s), 3.76-4.04(2H, broad m), 4.29-4.41 (2H, m), 4.62 (⅖H, broad d, J=10.4 Hz), 4.75(⅗H, broad), 4.62 (⅗H, broad d, J=14.6 Hz), 5.90 (⅖H, broad), 6.97 (1H,s), 7.29 (1H, dd, J=1.9, 8.7 Hz), 7.41 (1H, broad m), 7.63 (1H, s).

[6274] MS (FAB) m/z: 593 (M+H)⁺.

Example B-1991-[(5-Chloroindol-2-yl)sulfonyl]-4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl]carbonyl]piperazineHydrochloride

[6275] In the same manner as in Example B-82, the title compound wasobtained.

[6276]¹H-NMR (DMSO-d₆) δ: 2.65 (3H, br s), 2.76 (3H, br s), 3.13 (4H, brs), 3.74 (2H, br s), 4.10-4.50 (6H, br), 7.03 (1H, d, J=1.5 Hz), 7.31(1H, dd, J=8.8, 2.0 Hz), 7.48 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=2.0 Hz),12.42 (1H, br s).

[6277] MS (FAB) m/z: 495 [(M+H)⁺, Cl³⁵], 497 [(M+H)⁺, Cl³⁷].

Example B-2002-[[(4-tert-Butoxycarbonylpiperazin-1-yl)carbonyl]methyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6278] In the same manner as in Example B-79, the title compound wasobtained.

[6279]¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.49 (3H, s), 2.55-3.20 (8H, m),3.30-3.85 (12H, m), 3.95-4.04 (0.5H, m), 4.10-4.18 (0.5H, m), 4.55-4.67(0.5H, m), 4.95-5.07 (0.5H, m), 5.55-5.65 (0.5H, m), 6.00-6.10 (0.5H,m), 7.00 (1H, s), 7.25-7.31 (1H, m), 7.37 (1H, d, J=8.8 Hz), 7.65 (1H,s).

[6280] MS (FAB) m/z: 706 [(M+H)⁺, Cl³⁵], 708 [(M+H)⁺, Cl³⁷].

Example B-2014-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-2-[[(piperazin-1-yl)carbonyl]methyl]piperazineHydrochloride

[6281] In the same manner as in Example B-1, the title compound wasobtained.

[6282]¹H-NMR (DMSO-d₆) δ: 2.50-3.85 (23H, m), 4.30-4.45 (1H, m),4.60-4.75 (0.5H, m), 5.00-5.10 (0.5H, m), 5.30-5.40 (0.5H, m), 5.80-5.95(0.5H, m), 7.03 (1H, s), 7.32 (1H, d, J=8.8 Hz), 7.50 (1H, d, J=8.8 Hz),7.78 (1H, s), 9.20-9.45 (1H, br), 12.46 (1H, br s).

[6283] MS (FAB) m/z: 606 [(M+H)⁺, Cl³⁵], 608 [(M+H)⁺, Cl³⁷].

Example B-2024-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-furfurylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6284] In the same manner as in Example B-79, the title compound wasobtained.

[6285]¹H-NMR (DMSO-d₆) δ: 2.50-3.50 (13H, m), 3.60-3.85 (2H, m),4.12-4.50 (3H, m), 4.60-4.75 (0.5H, m), 5.05-5.10 (0.5H, m), 5.30-5.40(0.5H, m), 5.78-5.90 (0.5H, m), 6.17-6.25 (1H, br), 6.35-6.42 (1H, m),7.03 (1H, s), 7.31 (1H, d, J=8.8 Hz), 7.48 (1H, d, J=8.8 Hz), 7.51-7.58(1H, m), 7.77 (1H, s), 8.41-8.55 (1H, br), 12.44 (1H, br s)

[6286] MS (FAB) m/z: δ 17 [(M+H)⁺, Cl³⁵], 619 [(M+H)⁺, Cl³⁷.

[6287] HRMS (FAB) m/z: 617.1418 (M+H)⁺ (calcd for C₂₇H₂₉ClN₆O₅S₂,617.1408).

Example B-2034-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methoxy-N-methylcarbamoyl)methyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6288] In the same manner as in Example B-79, the title compound wasobtained.

[6289]¹H-NMR (DMSO-d₆) δ: 2.50-3.83 (20H, m), 4.30-4.80 (2.5H, br), 5.07(0.5H, br s), 5.31-5.36 (0.5H, br), 5.78 (0.5H, br s), 7.03 (1H, s),7.31 (1H, d, J=9.2 Hz), 7.48 (1H, d, J=9.2 Hz), 7.77 (1H, s), 11.04 (1H,br s), 12.45 (1H, br s).

[6290] MS (FAB) m/z: 581 [(M+H)⁺, Cl³⁵], 583 [(M+H)⁺, Cl³⁷].

Example B-2041-[(6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine

[6291] In the same manner as in Example B-62, the title compound wasobtained.

[6292]¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.85 (2H, br s), 3.22 (4H, br s),3.73 (2H, br s), 3.89 (2H, br s), 4.58 (2H, br s), 4.65 (2H, br s), 6.97(1H, s), 7.32 (1H, dd, J=8.8, 2.0 Hz), 7.37 (1H, d, J=8.8 Hz), 7.66 (1H,d, J=2.0 Hz), 8.72 (1H, s).

[6293] MS (FAB) m/z: 566 [(M+H)⁺, Cl³⁵], 568 [(M+H)⁺, Cl³⁷].

Example B-2051-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6294] In the same manner as in Example B-1, the title compound wasobtained.

[6295]¹H-NMR (DMSO-d₆) δ: 3.01 (2H, t, J=6.1 Hz), 3.13 (4H, br s), 3.44(2H, t, J=6.1 Hz), 3.75 (2H, br s), 4.36 (2H, br s), 4.42 (2H, s), 7.04(1H, s), 7.31 (1H, dd, J=8.8, 2.0 Hz), 7.49 (1H, d, J=8.8 Hz), 7.77 (1H,d, J=2.0 Hz), 9.46 (2H, br s), 12.43 (1H, s).

[6296] MS (FAB) m/z: 466 [(M+H)⁺, Cl³⁵], 468 [(M+H)⁺, Cl³⁷].

Example B-2061-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6297] In the same manner as in Example B-144, the title compound wasobtained.

[6298]¹H-NMR (DMSO-d₆) δ: 2.70-3.05 (2H, br), 3.05-3.25 (6H, br),3.65-4.50 (6H, br), 7.03 (1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.47(1H, d, J=8.8 Hz), 7.76 (1H, d, J=2.0 Hz), 8.35 (1H, s), 12.40 (1H, s)

[6299] MS (FAB) m/z: 482 [(M+H)⁺, Cl³⁵], 484 [(M+H)⁺, Cl³⁷].

Example B-2074-[(5-Chloroindol-2-yl)sulfonyl]-2-[(ethoxycarbonyl)methyl]-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6300] In a saturated solution of hydrochloride in ethanol was dissolved1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(methoxycarbonyl)methyl]piperazine(1.15 g), followed by stirring at room temperature for 1 hour. Thesolvent was distilled off under reduced pressure. Methylene chloride anda saturated aqueous solution of sodium bicarbonate were added to theresidue to separate into layers. The organic layer was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. A portion (519 mg) of the residue (0.97 g) was dissolved inN,N-dimethylformamide (2 ml), followed by the addition of lithium(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxylate(328 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(288 mg) and 1-hydroxybenzotriazole (363 mg). The resulting mixture wasstirred at room temperature for 3 days. Methylene chloride and waterwere added and the organic layer was collected. The organic layer wasdried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by flash columnchromatography (hexane:ethyl acetate=1:1) using as a carrier silica gel.

[6301] The resulting purified product was dissolved in a saturatedsolution (5 ml) of hydrochloride in ethanol, followed by stirring atroom temperature for 1 hour. After the addition of methylene chloride,the resulting mixture was washed with a saturated aqueous solution ofsodium bicarbonate. The organic layer was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was dissolved in methylene chloride (5 ml), followed by theaddition of methanesulfonyl chloride (105 μl) and triethylamine (0.5ml). The resulting mixture was stirred at room temperature for 15minutes and washed with water. The organic layer was dried overanhydrous sodium sulfate and distilled under reduced pressure to removethe solvent. The residue was purified by flash column chromatography(methylene chloride:methanol=49:1) using as a carrier silica gel,whereby the title compound (207 mg) was obtained.

[6302]¹H-NMR (DMSO-d₆) δ: 1.07-1.16 (3H, m), 2.67-2.90 (5H, m), 2.96(3H, s), 3.20-3.24 (2H, m), 3.53-3.78 (4H, m), 3.95-4.04 (2H, m), 4.39,5.04 (1H, each d, J=14.4, 14.9 Hz), 4.55 (2H, s), 5.03, 5.95 (1H, eachbr s), 7.03 (1H, s), 7.31 (1H, dd, J=8.8, 1.7 Hz), 7.47 (1H, d, J=8.8Hz), 7.76 (1H, d, J=1.7 Hz), 12.41 (1H, s).

[6303] MS (FAB) m/z: 630 (M+H)⁺.

Example B-2082-[Carboxymethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6304] In the same manner as in Example B-77, the title compound wasobtained.

[6305]¹H-NMR (DMSO-d₆) δ: 2.32-3.74 (14H, m), 4.38, 5.37 (1H, each d,J=12.2, 12.4 Hz), 4.54 (2H, s), 5.00, 5.83 (1H, each br s), 7.02 (1H,s), 7.30 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=8.8 Hz), 7.75 (1H, s), 12.51(1H, s).

[6306] HRMS (FAB) m/z: 602.0612 (M+H)⁺ (calcd for C₂₂H₂₅N₅O₇C1S₃,602.0605).

Example B-2094-[(5-Chloroindol-2-yl)sulfonyl]-2-[[N-methylsulfonyl)carbamoyl]methyl]-1-[(6-methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine

[6307] In tetrahydrofuran (5 ml) was dissolved2-[carboxymethyl]-4-[(5-chloroindol-2-yl)sulfonyl]-1-[(6-methylsulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine(115 mg), followed by the addition of carbonyldiimidazole (58 mg). Theresulting mixture was heated under reflux for 2 hours. After cooling toroom temperature, methanesulfonamide (34 mg) and1,8-diazabicyclo[5.4.0]-7-undecene (55 mg) were added, followed bystirring for 1.5 hours. The solvent was distilled off under reducedpressure. The residue was dissolved in methylene chloride and thesolution was washed with water, 0.2N hydrochloric acid and saturatedaqueous NaCl solution. The organic layer was dried over anhydrous sodiumsulfate and distilled under reduced pressure to remove the solvent. Theresidue was purified by preparative TLC (methylenechloride:methanol=9:1). The solvent was distilled off under reducedpressure. The solid thus obtained was washed with ether, whereby thetitle compound (62 mg) was obtained as a colorless solid.

[6308]¹H-NMR (DMSO-d₆) δ: 2.50-3.56 (15H, m), 3.65-3.77 (2H, m), 4.40,5.40 (1H, each d, J=15.4, 11.8 Hz), 4.55 (2H, s), 5.10, 5.98 (1H, eachbr s), 7.04 (1H, s), 7.31 (1H, d, J=8.8, 2.0 Hz), 7.47 (1H, d, J=8.8Hz), 7.76 (1H, d, J=2.0 Hz), 11.88 (1H, s), 12.44 (1H, s).

[6309] MS (FAB) m/z: 602 (M+H)⁺.

Example B-2101-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6310] To a solution of lithium6-(tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate(1.89 g) in N,N-dimethylformamide (40 ml) were added1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazine (2.50 g),1-hydroxybenzotriazole monohydrate (1.20 g) and1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.70 g) atroom temperature. After stirring for 2 days, ethyl acetate (200 ml) andwater (1.01) were added to the reaction mixture to separate it intolayers. The water layer was extracted with ethyl acetate (2×150 ml). Theorganic layers were combined, washed with water (1.0 l) and a saturatedaqueous solution (200 ml) of sodium bicarbonate, dried over anhydroussodium sulfate and distilled under reduced pressure to remove thesolvent. The residue was purified by chromatography on a silica gelcolumn (silica gel: 200 g, methylene chloride:ethyl acetate=7:1→1:1),whereby1-[[6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperazinewas obtained as pale yellow foam. A solution of the boc form inmethylene chloride (15 ml) was added trifluoroacetic acid (15 ml) atroom temperature. After stirring for 10 minutes, the solvent wasdistilled off under reduced pressure. Methylene chloride (50 ml) and asaturated aqueous solution (150 ml) of sodium bicarbonate were added tothe residue to separate it into layers. The water layer was extractedwith methylene chloride (6×25 ml). The organic layers were combined,dried over anhydrous sodium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column (silica gel: 100 g, methylenechloride:methanol=25:1→10:1), whereby the title compound (754 mg) wasobtained as a pale brown solid.

[6311]¹H-NMR (DMSO-d₆) δ: 2.67 (2H, t, J=5.7 Hz), 2.96 (2H, t, J=5.7Hz), 3.18 (4H, t, J=4.9 Hz), 3.31 (1H, s), 3.77 (2H, br s), 3.90 (2H,s), 4.44 (2H, br s), 7.57 (1H, dd, J=8.8, 2.0 Hz), 8.05 (1H, d, J=8.8Hz), 8.09 (1H, s), 8.31 (1H, d, J=2.0 Hz).

[6312] MS (FAB) m/z: 483 (M+H)⁺.

Example B-2111-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-4-[[6-(pyridin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6313] To a solution of1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine(200 mg) in N,N-dimethylformamide (2.0 ml) were added 4-bromopyridine(87.0 mg) and triethylamine (150 μl) at room temperature. The resultingmixture was stirred under heat at 120° C. for 12 hours. Afterconcentration of the reaction mixture, methylene chloride (20 ml), asaturated aqueous solution (50 ml) of sodium bicarbonate and water (50ml) were added to the concentrate to separate it into layers. The waterlayer thus obtained was extracted with methylene chloride (4×20 ml). Theorganic layers were combined, dried over anhydrous sodium sulfate anddistilled under reduced pressure to remove the solvent. The residue waspurified by preparative thin-layer chromatography (methylenechloride:methanol=20:1) using silica gel, followed by purification bypreparative thin-layer chromatography (methylenechloride:acetone:methanol=15:5:1) using silica gel. The purified productwas dissolved in methylene chloride, methanol and 1N hydrochloric acid.The resulting solution was concentrated under reduced pressure anddried, whereby the title compound (56.5 mg) was obtained as a paleyellow solid.

[6314]¹H-NMR (DMSO-d₆) δ: 2.97 (2H, t, J=5.6 Hz), 3.17 (4H, br s), 3.77(2H, br s), 4.05 (2H, t, J=5.6 Hz), 4.41 (2H, br s), 5.01 (2H, s), 7.31(2H, br s), 7.56 (1H, d, J=8.4 Hz), 8.05 (1H, d, J=8.4 Hz), 8.08 (1H,s), 8.30 (2H, s), 8.32 (1H, s), 13.70 (1H, br s).

[6315] MS (FAB) m/z: 560 (M+H)⁺.

Example B-2122-(Methoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[[5-(trimethylsilylethynyl)indol-2-yl]sulfonyl]piperazine

[6316] In the same manner as in Example B-62, the title compound wasobtained.

[6317]¹H-NMR (CDCl₃) δ: 0.26 (9H, s), 2.49 (3H, s), 2.53-2.68 (1H, m),2.74 (1H, dd, J=12.0, 2.7 Hz), 2.77-2.83 (3H, m), 2.87 (2H, br s), 3.00(1H, dd, J=15.8, 8.7 Hz), 3.11-3.26 (½H, br), 3.39-3.54 (½H, br),3.59-3.67 (5H, m), 3.72-3.96 (2H, m), 4.61 (½H, br d, J=13.2 Hz), 5.22(½H, br s), 5.71 (½H, br d, J=13.2 Hz), 6.16 (½H, br s), 6.97 (1H, s),7.34 (1H, d, J=8.6 Hz), 7.43 (1H, dd, J=8.6, 1.5 Hz), 7.81 (1H, s), 9.35(1H, br d, J=11.0 Hz).

[6318] MS (FAB) m/z: 614 (M+H)⁺.

Example B-2134-[(5-Ethynylindol-2-yl)sulfonyl-2-(methoxycarbonylmethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6319] In the same manner as in Example B-104, the title compound wasobtained.

[6320]¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 2.53-2.95 (7H, m), 2.95-3.05 (1H,m), 3.04 (1H, s), 3.20 (½H, br t, J=11.6 Hz), 3.46 (½H, br t, J=11.6Hz), 3.59-3.75 (5H, m), 3.75-3.97 (2H, m), 4.62 (½H, br d, J=12.8 Hz),5.22 (½H, br s), 5.73 (½H, br d, J=13.6 Hz), 6.18 (½H, br s), 7.00 (1H,s), 7.37 (1H, d, J=8.6 Hz), 7.45 (1H, dd, J=8.6, 1.2 Hz), 7.85 (1H, s),9.28 (1H, br d, J=13.2 Hz).

[6321] MS (FAB) m/z: 542 (M+H)⁺.

Example B-2144-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[2-(morpholin-4-yl)sulfonyl]ethyl]piperazineHydrochloride

[6322] In the same manner as in Example B-182, the title compound wasobtained.

[6323]¹H-NMR (DMSO-d₆) δ: 2.10-2.40 (2H, m), 2.50-2.80 (2H, m), 2.90(3H, s), 3.00-3.30 (8H, m), 3.30-3.90 (9H, s), 4.30-4.90 (3H, m),5.30-5.50 (1H, m), 7.03 (1H, s), 7.31 (1H, dd, J=8.8, 1.5 Hz), 7.48 (1H,d, J=8.8 Hz), 7.76 (1H, d, J=1.5 Hz), 11.42 (1H, br), 12.45 (1H, s).

[6324] MS (FAB) m/z: 657 [(M+H)⁺, Cl³⁵], 659 [(M+H)⁺, Cl³⁷].

Example B-2154-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-ethoxycarbonylethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6325] In the same manner as in Example B-62, the title compound wasobtained.

[6326]¹H-NMR (CDCl₃) δ: 1.15-1.25 (3H, m), 1.40-1.80 (1H, m), 2.05-2.15(1H, m), 2.25-2.45 (3H, m), 2.49 (3H, s), 2.50-3.55 (6H, m), 3.67 (2H,s), 3.70-3.90 (2H, m), 4.00-4.20 (2H, m), 4.55-6.10 (2H, m), 6.95 (1H,s), 7.30-7.40 (2H, m), 7.65 (1H, d, J=1.6 Hz), 9.03 (1H, br).

[6327] MS (FAB) m/z: 580 [(M+H)⁺, Cl³⁵], 582 [(M+H)⁺, Cl³⁷].

Example B-2164-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[2-(morpholin-4-yl)carbonyl]ethyl]piperazine

[6328] In the same manner as in Referential Example 319, the titlecompound was obtained.

[6329]¹H-NMR (DMSO-d₆) δ: 1.85-2.00 (1H, m), 2.05-2.20 (1H, m),2.20-2.35 (2H, m), 2.55-2.70 (1H, m), 3.80-2.95 (4H, m), 3.00-3.80 (14H,m), 4.25-5.55 (5H, m), 7.02 (1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.48(1H, d, J=8.8 Hz), 7.75 (1H, d, J=2.0 Hz), 11.45 (1H, br s), 12.43 (1H,s).

[6330] MS (FAB) m/z: 621 [(M+H)⁺, Cl³⁵], 623 [(M+H)⁺, Cl³⁷].

Example B-2174-[(5-Chloroindol-2-yl)sulfonyl]-2-[[2(N,N-dimethylaminocarbonyl)ethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6331] In the same manner as in Referential Example 319, the titlecompound was obtained.

[6332]¹H-NMR (DMSO-d₆) δ: 1.85-2.00 (1H, m), 2.05-2.20 (1H, m),2.20-2.35 (2H, m), 2.50-2.65 (1H, m), 2.70-3.80 (17H, m), 4.30-5.55 (4H,m), 7.02 (1H, s), 7.29 (1H, dd, J=8.8, 2.0 Hz), 7.48 (1H, d, J=8.8 Hz),7.75 (1H, d, J=2.0 Hz), 11.49 (1H, br s), 12.44 (1H, s)

[6333] MS (FAB) m/z: 579 [(M+H)⁺, Cl³⁵], 581 [(M+H)⁺, Cl³⁷].

Example B-2184-[(5-Chloroindol-2-yl)sulfonyl]-2-(2-cyanoethyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazineHydrochloride

[6334] In the same manner as in Example B-182, the title compound wasobtained.

[6335]¹H-NMR (DMSO-d₆) δ: 1.90-2.18 (2H, m), 2.20-2.90 (4H, m), 2.90(3H, s) 3.12 (2H, br s), 3.21-3.82 (6H, m), 4.30-4.85 (2H, m), 5.31-5.43(0.5H, m), 5.55-5.70 (0.5H, m), 7.02 (1H, d, J=2.0 Hz), 7.31 (1H, dd,J=8.9, 2.1 Hz), 7.48 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=1.7 Hz), 11.18(1H, br s), 12.44 (1H, br s).

[6336] MS (FAB) m/z: 533 [(M+H)⁺, Cl³⁵], 535 [(M+H)⁺, Cl³⁷].

Example B-2191-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbonyl]piperazine

[6337] In the same manner as in Example B-62, the title compound wasobtained.

[6338]¹H-NMR (DMSO-d₆) δ: 1.93 (2H, t, J=6.6 Hz), 2.73-3.32 (10H, m),3.73 (1H, br s), 3.93 (4H, s), 3.95 (1H, br s), 6.97, 7.03 (1H, s), 7.30(1H, dd, J=8.8, 2.2 Hz), 7.45-7.47 (1H, m), 7.76 (1H, s).

[6339] MS (FAB) m/z: 523 [(M+H)⁺, Cl³⁵], 525 [(M+H)⁺, Cl³⁷].

Example B-2201-[(5-Chloroindol-2-yl)sulfonyl]-4-[(6-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbonyl]piperazine

[6340] In a 300-mL egg-plant type flask was charged1-[(5-chloroindol-2-yl)sulfonyl]-4-[(6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbonyl]piperazine(740 mg), followed by dissolution in methanol (150 mL). To the resultingsolution was added p-toluenesulfonic monohydrate (100 mg), followed byheating under reflux. After 16 hours, the reaction was terminated andthe solvent was distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column (silica gel: 75 g,ethyl acetate:hexane=1:1), whereby the title compound (110 mg) wasobtained as a pale yellow amorphous solid.

[6341]¹H-NMR (CDCl₃) δ: 2.76 (2H, t, J=6.8 Hz), 3.18 (2H, t, J=6.8 Hz),3.19-3.22 (6H, m), 3.65 (2H, s), 3.89 (1H, br s), 4.59 (1H, br s), 6.97(1H, s), 7.31-7.39 (2H, m), 7.66 (1H, d, J=2.0 Hz).

[6342] MS (FAB) m/z: 479 [(M+H)⁺, Cl³⁵], 481 [(M+H)⁺, Cl³⁷].

Example B-2211-[(5-Chloroindol-2-yl)sulfonyl]-4-[(4,5-dihydro-7H-pyrano[4,3-d]thiazol-2-yl)carbonyl]piperazine

[6343] In the same manner as in Example B-62, the title compound wasobtained.

[6344]¹H-NMR (DMSO-d₆) δ: 2.82 (2H, t, J=5.6 Hz), 3.12 (4H, t, J=4.9Hz), 3.28-3.35 (2H, m), 3.73 (1H, br s), 3.93 (2H, t, J=5.6 Hz), 4.39(1H, br s), 4.79 (2H, s), 7.03 (1H, s), 7.30 (1H, dd, J=8.8, 2.2 Hz),7.47 (1H, d, J=8.8 Hz), 7.76 (1H, s).

[6345] MS (FAB) m/z: 467 [(M+H)⁺, Cl³⁵], 469 [(M+H)⁺, Cl³⁷].

Example B-2224-[(5-Chloroindol-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[N-(phenylsulfonyl)carbamoyl]methyl]piperazineHydrochloride

[6346] In the same manner as in Example B-62, the title compound wasobtained.

[6347]¹H-NMR (DMSO-d₆) δ: 2.52-3.77 (12H, m), 3.88-4.20 (2H, m),4.24-4.48 (1.5H, m), 4.52-4.75 (1H, m), 5.00 (0.5H, m), 5.23-5.32 (0.5H,m), 5.57 (0.25H, br s), 5.79 (0.25H, br s), 6.97 (1H, s), 7.28 (1H, d,J=8.8 Hz), 7.45 (1H, d, J=8.8 Hz), 7.49-7.53 (1H, m), 7.61 (2H, br s),7.72 (1H, s), 7.85 (2H, br s), 11.54-11.98 (1H, m), 12.20-12.50 (2H, m).

[6348] MS (FAB) m/z: 677 [(M+H)⁺, Cl³⁵], 679 [(M+H)⁺, Cl³⁷].

Example B-2231-[(5-Chloroindol-2-yl)sulfonyl]-2-[(N-methyl-N-methylsulfonylcarbamoyl)methyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6349] In the same manner as in Example B-62, the title compound wasobtained.

[6350]¹H-NMR (DMSO-d₆) δ: 3.12-4.53 (21H, m), 3.75-3.82 (0.5H, m),4.35-4.45 (1H, m), 5.09 (0.5H, br s), 5.32-5.49 (0.5H, m), 5.85 (0.5H,br s), 7.02 (1H, s), 7.30 (1H, dd, J=8.8, 2.0 Hz), 7.47 (1H, dd, J=8.8,2.0 Hz), 7.75 (1H, s), 12.44 (1H, br s).

[6351] MS (FAB) m/z: 629 [(M+H)⁺, Cl³⁵], 631 [(M+H)⁺, Cl³⁷].

Example B-2244-(5-Chloroindol-2-yl)sulfonyl]-2-[(2-methylsulfonylhyrazino)carbonylmethyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazineHydrochloride

[6352] In the same manner as in Example B-62, the title compound wasobtained.

[6353]¹H-NMR (DMSO-d₆) δ: 3.10-4.60 (17H, m), 5.10-5.25 (1.5H, m),5.40-5.55 (1H, m), 5.90 (0.5H, br s), 6.11-6.20 (0.5H, m), 6.74 (0.5H,br s), 7.81 (1H, s), 8.10 (1H, d, J=8.6 Hz), 8.27 (1H, d, J=8.6 Hz),8.56 (1H, s), 10.15-10.25 (1H, m), 11.08 (1H, s), 11.99 (1H, s), 13.22(1H, s).

[6354] MS (FAB) m/z: 630 [(M+H)⁺, Cl³⁵], 632 [(M+H)⁺, Cl³⁷].

Example B-2251-[[5(6)-chlorobenzimidazol-2-yl]sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine

[6355] 1-[[5(6)-chlorobenzimidazol-2-yl-]sulfonyl]pyperazine (225 mg),1-hydroxybenztriazole (11 mg) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (148 mg) weresuccessively added to a N,N-dimethylformamide soulution (3.0 ml)containing lithium6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carboxylate (153mg), and stirred at room temperature for 28 hours. After concentrationunder reduced pressure, the reaction solution was divided into twolayers by adding a dichloromethane and saturated sodium chloridesolution. The organic layer was washed with a saturated sodium chloridesolution, dried over sodium sulfate, and concentrated under reducedpressure. The obtained product was purified by chromatography on asilica gel column (dichloromethane:methanol=20:1), concentrated byadding ethanol (2 ml) and a 1N aqueous hydrochloride in ethanol (1.5ml), and dried. Thus, the title compound (168 mg) was obtained ascolorless amorphous.

[6356] IR(KBr)cm⁻¹ 1622, 1429, 1365, 1279, 1157, 1055, 1005, 970, 939,922.

[6357]¹H-NMR (DMSO-d₆) d, 2.90 (3H, s), 3.03-4.00 (10H, br), 4.40 (3H,br s), 4.63-4.77 (1H, m), 7.40 (1H, dd, J=8.8, 2.0 Hz), 7.72 (1H, d,J=8.8 Hz), 7.78 (1H, s), 11.48-11.65 (1H, br s).

[6358] MS (FAB) m/z 481 [(M+H)⁺, Cl³⁵], 483 [(M+H)⁺, Cl³⁷].

[6359] [Test 1] Measurement of FXa Inhibitory Action (IC₅₀)

[6360] In a 96-well microtiter plate, 10 μl of a sample solution, 40 μlof a 100 mM tris.200 mM sodium chloride.0.2% BSA (pH: 7.4) buffer and 10μl of 0.05 U/ml human FXa (“Cosmobio-ERL HFXa-1011”, dissolved in anddiluted with a measuring buffer) were poured in portions, followed bythe addition of 40 ml of 750 μM S2222 (product of Chromogenix). Anincrease (mOD/min) in the absorbance at 405 nm was measured at roomtemperature. From the below-described equation, an inhibitory ratio % ofeach sample was determined. On a logarithmic probability paper, thefinal concentration of the sample and inhibitory ratio % were plottedalong the abscissa and the ordinate, respectively, whereby a 50%inhibitory concentration (IC₅₀) was determined.

Inhibitory ratio (%)=(1−OD of sample÷OD of control)×100

[6361] (Results)

[6362] The compound of the formula (I) having, in the structure thereof,an unsubstituted pyridylphenyl group as the group Q¹-Q²- and a7-chloronaphthyl, 5-chlorobenzofuranyl, 6-chlorobenzofuranyl,5-chlorobenzothienyl or 5-chloro-1-methylindole group as the group Q^(A)is found to have FXa activity 50% inhibitory concentration (IC₅₀) of 100nM or greater (refer to Table 1). TABLE 1 Concentration (nM) of thesample at which 50% of Fxa Sample compound activity is inhibitedCompound of Example 123 A-1 Compound of Example 180 A-17 Compound ofExample 2800 A-83 Compound of Example 1000 A-85 Compound ofExample >10000 A-86 Compound of Example 7000 A-91 Compound of Example450 A-96 Compound of Example 420 A-106

[6363] The compound similar to the compound of Example A-1 except forhaving a substituted pyridylphenyl group, pyridylpyrimidinyl group,pyridylpyrazyl group or pyridylpyridyl group instead of thepyridylphenyl group is found to have FXa inhibitory action improved byseveral times as much as that of the compound of Example A-1 (refer toTable 2). TABLE 2 Concentration (nM) of the sample at which 50% ofSample compound Fxa activity is inhibited Compound of Example 38 A-152Compound of Example 28 A-155 Compound of Example 23 A-123 Compound ofExample 60 A-137 Compound of Example 54 A-4

[6364] The compound similar to that of Example A-1 except for having, asthe group Q^(A), a 6-chlorobenzothienyl group, 5-ethynylindolyl group or5-chloroindolyl group instead of chloronaphthyl group is found to beparticularly excellent in FXa inhibitory action (refer to Table 3).TABLE 3 Concentration (nM) of the sample at which 50% of Sample compoundFxa activity is inhibited Compound of Example 16 A-90 Compound ofExample 9.5 A-101 Compound of Example 27 A-103 Compound of Example 15A-181 Compound of Example 82 A-97 Compound of Example 125 A-98

[6365] The compound having, as the group Q¹-Q²-, a pyridylphenyl groupis found to show a drastic improvement in the FXa inhibitory action whenthe nitrogen atom on the pyridine ring has been converted into N-oxideand the group Q^(A) represents a 6-chlorobenzothienyl group,5-ethynylindolyl group or 5-chloroindolyl group (refer to Table 4).TABLE 4 Concentration (nM) of the sample at which 50% of Sample compoundFxa activity is inhibited Compound of Example 4.7 A-107 Compound ofExample 10.5 A-117 Compound of Example 6.9 A-109 Compound of Example 8.6A-116 Compound of Example 2.9 A-181 Compound of Example 14 A-120

[6366] The compound having, as the group Q¹-Q²-, a heteroaryl group suchas pyridylpyrimidinyl, pyridylpyrazinyl or pyridylthiazolyl group and,as the group Q^(A), a 6-chlorobenzothienyl, 6-ethynylbenzothienyl,5-chloroindolyl or 5-ethynylindolyl group is found to be improved in FXainhibitory action (refer to Table 5). TABLE 5 Concentration (nM) of thesample at which 50% of Sample compound Fxa activity is inhibitedCompound of Example 5.6 A-132 Compound of Example 10 A-133 Compound ofExample 2.4 A-105 Compound of Example 4.6 A-134 Compound of Example 5A-138 Compound of Example 6.8 A-140 Compound of Example 19 A-131Compound of Example 14 A-135 Compound of Example 4.7 A-183 Compound ofExample 6.3 A-185 Compound of Example 1.9 A-186 Compound of Example 1.6A-229 Compound of Example 2.3 A-231 Compound of Example 3.5 A-239Compound of Example 15 A-216 Compound of Example 1.3 A-296

[6367] The compound having one or two substituents introduced in thegroup Q³ is found to exhibit strong FXa inhibitory activity (refer toTable 6). TABLE 6 Concentration (nM) of the sample at which 50% ofSample compound Fxa activity is inhibited Compound of Example 3.6 A-130Compound of Example 10 A-173 Compound of Example 20 A-105 Compound ofExample 7.6 A-224 Compound of Example 3.5 A-259 Compound of Example 2.7A-277 Compound of Example 10 A-279 Compound of Example 1.9 A-293Compound of Example 0.7 A-298

[6368] Compounds of Examples B-32, B-54, B-61, B-63 and B-99 exhibitedFXa 50% inhibitory concentrations of 20 nM, 5.0 nM, 30 nM, 12.5 nM and1.7 nM, respectively.

[6369] [Test 2] Measurement of Thrombin Inhibitory Action (IC₅₀)

[6370] In a 96-well microtiter plate, 10 ul of a sample solution, 40 μlof a 100 mM tris.200 mM sodium chloride.0.2% BSA (pH: 7.4) buffer and 10μl of 4 U/ml human thrombin (Sigma Chemical, dissolved in and dilutedwith a measuring buffer) were poured in portions, followed by theaddition of 40 μl of 500 μM S2266 (product of Chromogenix). An increase(mOD/min) in the absorbance at 405 nm was measured at room temperature.From the below-described equation, an inhibitory ratio % of each samplewas determined. On a logarithmic probability paper, the finalconcentration of the sample and inhibitory ratio % were plotted alongthe abscissa and the ordinate, respectively, whereby a 50% inhibitoryconcentration (IC₅₀) was found.

Inhibitory ratio (%)=(1−OD of sample÷OD of control)×100

[6371] The compound having, in the structure thereof, a heteroaryl groupsuch as pyridylpyrimidinyl or pyridylpyrazinyl, a 6-chlorobenzothienylgroup, a 6-ethynylbenzothienyl, a 5-ethynylindolyl group or a5-chloroindolyl group; or the compound having, in the structure thereof,a 6-chlorobenzothienyl, 6-ethynylbenzothienyl, 5-ethynylindolyl or5-chloroindolyl group, in addition to a heteroaryl group such aspyridylpyrimidinyl or pyridylpyrazinyl is found to exhibit markedly lowthrombin-activity inhibitory action compared with excellent FXainhibitory action (refer to Tables 7 and 8). TABLE 7 Concentration (nM)of the sample at which 50% of thrombin Sample compound activity isinhibited Compound of Example 4100 A-117 Compound of Example 4100 A-137Compound of Example 16000 A-123 Compound of Example 1550 A-109 Compoundof Example >100000 A-132 Compound of Example 7700 A-133 Compound ofExample >50000 A-216

[6372] TABLE 8 Concentration (nM) of the sample at which 50% of Samplecompound thrombin action is inhibited Compound of Example 19000 A-105Compound of Example 10200 A-134 Compound of Example 5900 A-138 Compoundof Example 1370 A-140 Compound of Example 2220 A-103

[6373] The compound of Example B-54 exhibited a thrombin 50% inhibitoryconcentration of 1.05 μM.

[6374] [Test 3] Measurement of Coagulation Extending Action (Measurementof Prothrombin Time)

[6375] Plasma (20 μl) and 20 μl of a sample solution were 10 mixed. Tothe resulting mixture, 40 ml of cynplastin (product of Organon Teknika)was added and the coagulation time was measured. The concentration ofthe sample (CT2) at which the coagulation time of the plasma wasincreased twice was found and it was designated as an index ofanticoagulant action.

[6376] The compound of Example 33 showed CT2 of 0.35 μM.

[6377] [Test 4] Test of Oral Administration

[6378] 1) Method

[6379] A sample was dissolved or suspended in a 0.5% (w/v) methylcellulose solution and the resulting solution or suspension was orallyadministered (10 ml/kg) to a 8 to 11 week-old rat (Wistar male rat(Nippon SLC Co., Ltd.)) which had been fasted overnight. Afteradministration of the sample, the blood to which {fraction (1/10)} partby weight of 3.13% (w/v) sodium citrate had been added was collectedfrom the cervical vein under anesthesia with halothane. The rat wasawakened except during the blood collection. Feeding was re-started 6hours after the blood collection. From each blood sample, the plasma wasseparated by centrifugal separation and anti-FXa activity in the bloodand prothrombin time extending action were measured.

[6380] 2) Measuring Method

[6381] 2-1) Measurement of Anti-FXa Activity in the Plasma

[6382] In a 96-well plate, 5 μl of the plasma was poured in portions,followed by the addition of 55 μl of a 8:1:2 mixture of 100 mM tris.200mM sodium chloride.0.2% BSA (pH 7.4) buffer, water and 0.1 U/ml humanFactor Xa solution (dissolved in and diluted with a measuring buffer)and 40 μl of 750 μM S-2222. After stirring for 10 seconds in a platemixer, an increase (mOD/min) of the absorbance at 405 nm was measured atroom temperature. The inhibitory ratio was calculated as follows:

An inhibitory ratio (%)=(1−OD of sample÷OD of control on averagerelative to blood-collecting time of sample)×100

[6383] 2-2) Measurement of Coagulation Extending Action in OralAdministration (Measurement of Prothrombin Time)

[6384] To 20 μl of the plasma, 40 μl of cynplastin (Organon Teknika/USA)was added and the coagulation time was measured. The ratio of theprothrombin time after the administration of the sample relative to theprothrombin time before the administration of the sample was designatedas an index of the coagulation extending action.

[6385] 3) Results

[6386] The compound of Example A-60 showed an anti-FXa activity of 70%in the plasma one hour after the oral administration of 30 mg/kg of thesample. It extended the prothrombin time by 1.18 times.

[6387] The compound of Example B-36 showed an anti-FXa activity of 68%in the plasma one hour after the oral administration of 30 mg/kg of thesample. It extended the thrombin time.

[6388] [Test 5] Testing Method of Anti-Thrombus Effects in a TissueThromboplastin-Derived Rat DIC Model

[6389] A rat was anesthetized with halothane. After the collection ofthe blood (for measurement of the number of platelets, anti-FXa activityand TAT) from its cervical vein by using {fraction (1/10)} part byweight of 3.13% (w/v) sodium citrate, the sample was administeredorally. At an appropriate time after the administration, the rat wasintraperitoneally anesthetized (1 mg/kg) with Nembutal (50 mg/mlpentobarbital sodium, Abott Laboratories), followed by intravenous dripof 0.2 U/ml of tissue thromboplastin (Thromboplastin C plus, DadeDiagnostics of P. R. Inc.,) from the femoral vein for one minute at arate of 2.5 to 3.0 ml/kg/min. The blood was collected (for measuring thenumber of platelets and anti-FXa activity) from the cervical vein 10minutes after the intravenous drip and the blood was collected (formeasuring TAT) from the cervical vein 20 minutes after the bloodcollection. The number of platelets, anti-FXa activity in the plasma andTAT concentration of each blood sample were measured. The number of theplatelets was measured by an automatic cytometer, while the anti-FXaactivity in the plasma was measured in a similar manner to thatdescribed in Test 4.

[6390] For the measurement of TAT (Thrombin-anti Thrombin=complex),EnzygnostR TAT micro kit (Boering Verke) was employed.

[6391] As a result of the oral administration of 30 mg/kg of thecompound of Example B-36, apparent anti-FXa action in the plasma wasrecognized and a decrease in the number of the platelets and an increasein the TAT concentration were suppressed (the tissue thromboplastin wasadministered one hour after the administration of the sample).

[6392] Capability of Exploitation in Industry

[6393] The compound according to the present invention has peculiar andexcellent FXa inhibitory action so that it is useful as a coagulationsuppressor, or a preventive and/or remedy for thrombosis or embolism.

[6394] Use of the compound of the present invention as a pharmaceuticalcan therefore treat or prevent various diseases caused by a thrombus orembolus such as cerebral infarction, cerebral embolism, myocardialinfarction, pulmonary infarction, pulmonary embolism, Buerger's disease,deep vein thrombosis, disseminated intravascular coagulation syndrome,thrombus formation after valve replacement, reocclusion afterrevascularization, formation of a thrombus upon extracorporealcirculation or coagulation upon blood collection.

1. A sulfonyl derivative represented by the following formula (I):Q¹-Q²-T¹-Q³-SO₂-Q^(A)  (I) [wherein Q¹ represents a saturated orunsaturated 5- or 6-membered cyclic hydrocarbon group which may have asubstituent, a saturated or unsaturated 5- or 6-membered heterocyclicgroup which may have a substituent, a saturated or unsaturated dicyclicfused ring group which may have a substituent or a saturated orunsaturated tricyclic fused ring group which may have a substituent; Q²represents a single bond, an oxygen atom, a sulfur atom, a linear orbranched C₁₋₆ alkylene group, a linear or branched C₂₋₆ alkenylenegroup, a linear or branched C₂₋₆ alkynylene group, a group —N(R¹)—CO—(in which R¹ represents a hydrogen atom or an alkyl group), a group—N(R²)—(CH₂)_(m)— (in which R² represents a hydrogen atom or an alkylgroup and m stands for an integer of 0 to 6), or a group of thefollowing formula:

(which represents a divalent, saturated or unsaturated 5- or 6-memberedcyclic hydrocarbon group which may have a substituent, a divalent,saturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent, or a divalent, saturated or unsaturated dicyclicfused ring group which may have a substituent and ←C means the bondingof the carbon atom of this group to Q¹), Q³ represents any one of thefollowing groups:

(in which, when the carbon atom to which each of R³, R⁴, R⁵, R⁶, R⁷, R⁸,R¹⁰ and R¹¹ has been bonded is not adjacent to a nitrogen atom, R³, R⁴,R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ each independently represents a hydrogenatom, a hydroxyl group, an alkyl group, an alkoxyl group, an alkoxyalkylgroup, an alkoxyalkyloxy group, a hydroxyalkyl group, a hydroxyalkyloxygroup, a hydroxyalkylcarbonyl group, a hydroxyalkylsulfonyl group, aformyl group, a formylalkyl group, a formylalkylcarbonyl group, aformylalkylsulfonyl group, an alkylcarbonyl group, an alkylsulfonylgroup, an alkylcarbonylalkyl group, an alkylsulfonylalkyl group, acarboxyl group, a carboxyalkyl group, a carboxyalkyloxy group, acarboxyalkylcarbonyl group, a carboxyalkylsulfonyl group, acarboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkyl group, analkoxycarbonyl group, an alkoxycarbonylalkyl group, analkoxycarbonylalkyloxy group, an alkoxycarbonylalkylcarbonyl group, analkoxycarbonylalkylsulfonyl group, an amino group which may have one ortwo substituents, an aminoalkyl group which may have, at the aminomoiety thereof, one or two substituents, an aminoalkyloxy group whichmay have, at the amino moiety thereof, one or two substituents, anaminoalkylcarbonyl group which may have, at the amino moiety thereof,one or two substituents, an aminoalkylcarbonyloxy group which may have,at the amino moiety thereof, one or two substituents, an aminocarbonylgroup which may have, at the amino moiety thereof, one or twosubstituents, an aminocarbonylalkyl group which may have, at the aminomoiety thereof, one or two substituents, an aminocarbonylalkyloxy groupwhich may have, at the amino moiety thereof, one or two substituents, analkylsulfonylaminocarbonylalkyl group which may have, at the aminomoiety thereof, one substituent, an arylsulfonylaminocarbonyl groupwhich may have, at the amino moiety thereof, one substituent, anaminosulfonylalkyl group which may have, at the amino moiety thereof,one or two substituents, a cyanoalkyl group, analkoxyalkylaminocarbonylalkyl group which may have, at the amino moietythereof, one substituent, or a group A¹-B¹- (in which A¹ represents asaturated or unsaturated 5- or 6-membered cyclic hydrocarbon group whichmay have a substituent or a saturated or unsaturated 5- or 6-memberedheterocyclic group which may have a substituent and B¹ represents asingle bond, a carbonyl group, an alkylene group, a carbonylalkyl group,a group —O—C₁₋₆ -alkylene, a group —COO—C₁₋₆ alkylene, a group —NHCO— ora group —NHCO—(C₁₋₆ alkylene) group), when the carbon atom to which eachof R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ has been bonded is adjacent to anitrogen atom, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ each independentlyrepresents a hydrogen atom, an alkyl group, a hydroxyalkyl group, ahydroxyalkylcarbonyl group, a hydroxyalkylsulfonyl group, a formylgroup, a formylalkyl group a formylalkylcarbonyl group, aformylalkylsulfonyl group, an alkylcarbonyl group, an alkylsulfonylgroup, an alkylcarbonylalkyl group, an alkylsulfonylalkyl group, acarboxyl group, a carboxyalkyl group, a carboxyalkylcarbonyl group, acarboxyalkylsulfonyl group, a carboxyalkylcarbonylalkyl group, acarboxyalkylsulfonylalkyl group, an alkoxyalkyl group, an alkoxycarbonylgroup, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylcarbonylgroup, an alkoxycarbonylalkylsulfonyl group, an aminoalkyl group whichmay have, at the amino moiety thereof, one or two substituents, anaminoalkylcarbonyl group which may have, at the amino moiety thereof,one or two substituents, an aminocarbonyl group which may have, at theamino moiety thereof, one or two substituents, an aminocarbonylalkylgroup which may have, at the amino moiety thereof, one or twosubstituents, an alkylsulfonylaminocarbonylalkyl group which may have,at the amino moiety thereof, one substituent, anarylsulfonylaminocarbonyl group which may have, at the amino moietythereof, one substituent, an aminosulfonylalkyl group which may have, atthe amino moiety thereof, one or two substituents, a cyanoalkyl group,an alkoxyalkylaminocarbonylalkyl group which may have, at the aminomoiety thereof, one substituent, an alkylcarbonyloxyalkyl group, or agroup A²-B- (in which A² represents a saturated or unsaturated 5- or6-membered cyclic hydrocarbon group which may have a substituent or asaturated or unsaturated 5- or 6-membered heterocyclic group which mayhave a substituent, and B² represents a single bond, a carbonyl group,an alkylene group, a carbonylalkyl group, a group —O—C₁₋₆ alkylenegroup, a group —COO—C₁₋₆ alkylene group, a group —NHCO— or a group—NHCO—C₁₋₁₆ alkylene group), each of R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸,and R¹⁰ and R¹¹ may be coupled together with a carbon atom whichconstitutes the ring and represent a saturated or unsaturated 5- to7-membered cyclic hydrocarbon group which may have a substituent or asaturated or unsaturated 5- to 7-membered heterocyclic group which mayhave a substituent, R⁹ and R¹² each independently represents: a hydrogenatom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonylgroup, a hydroxyalkylsulfonyl group, an alkoxyl group, an alkoxyalkylgroup, an alkoxyalkylcarbonyl group, an alkoxyalkylsulfonyl group, aformyl group, a formylalkyl group, a formylalkylcarbonyl group, aformylalkylsulfonyl group, an alkylcarbonyl group, an alkylcarbonylalkylgroup, an alkylsulfonyl group, an alkylsulfonylalkyl group, acarboxyalkyl group, a carboxyalkylcarbonyl group, a carboxyalkylsulfonylgroup, a carboxyalkylcarbonylalkyl group, a carboxyalkylsulfonylalkylgroup, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, analkoxycarbonylalkylcarbonyl group, an alkoxycarbonylalkylsulfonyl group,an amino group which may have one or two substituents, an aminoalkylgroup which may have, at the amino moiety thereof, one or twosubstituents, an aminoalkyloxy group which may have, at the amino moietythereof, one or two substituents, an aminoalkylcarbonyl group which mayhave, at the amino moiety thereof, one or two substituents, anaminoalkyloxycarbonyl group which may have, at the amino moiety thereof,one or two substituents, an aminocarbonyl group which may have, at theamino moiety thereof, one or two substituents, an aminocarbonylalkylgroup which may have, at the amino moiety thereof, one or twosubstituents, an aminocarbonyloxyalkyl group which may have, at theamino moiety thereof, one or two substituents, analkylsulfonylaminocarbonylalkyl group which may have, at the aminomoiety thereof, one substituent, an arylsulfonylaminocarbonyl groupwhich may have, at the amino moiety thereof, one substituent, anaminosulfonylalkyl group which may have, at the amino moiety thereof,one or two substituents, a cyanoalkyl group, or analkoxyalkylaminocarbonylalkyl group which may have, at the amino moietythereof, one substituent, R⁹ and R⁷ or R⁸ may be coupled together with acarbon atom constituting the ring and a nitrogen atom to which R⁹ hasbeen bonded and represent a saturated or unsaturated 5- to 7-memberedheterocyclic group which may have a substituent, R¹² and R¹⁰ or R¹¹ maybe coupled together with a carbon atom constituting the ring and anitrogen atom to which R¹² has been bonded and represent a saturated orunsaturated 5 to 7-membered heterocyclic group which may have asubstituent, a, b, d, e and g each independently stands for an integerof 0 or 1, c stands for an integer of 0 to 3, and f, h and i eachindependently represents an integer of 1 to 3, with the proviso that thesum of a, b and c stands for an integer of 2 or 3, the sum of d and estands for an integer of 0 or 1 and the sum of f, g and h stands for aninteger of 3 to 5), Q^(A) represents an arylalkenyl group which may havea substituent, a heteroarylalkenyl group which may have a substituent, asaturated or unsaturated dicyclic fused ring group which may have asubstituent, a saturated or unsaturated tricyclic fused ring group whichmay have a substituent, a group Ar—C(H)═N— (in which, Ar represents anaryl group which may have a substituent), or a group Het-C(H)═N— (inwhich, Het represents a heteroaryl group which may have a substituent),and T¹ represents a carbonyl group, a group —CH(R¹³)— (in which Rrepresents a hydrogen atom, an alkyl group, a hydroxyalkyl group havingthe hydroxyl group which may be protected, an alkoxyalkyl group, acarboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, anaralkyl group, a heteroaryl group, a heteroarylalkyl group or anaminoalkyl group which may have, at the amino moiety thereof, asubstituent (protecting group)), or a group —C(═NOR¹⁴)— or—C(═N—NHR^(14′))— (in which R¹⁴ and R^(14′) independently represent ahydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonylgroup, an aryl group, an aralkyl group, a heteroaryl group, aheteroarylalkyl group or an aminoalkyl group which may have, at theamino moiety thereof, a substituent)], or salt thereof; or a solvatethereof.
 2. A sulfonyl derivative according to claim 1, wherein in theformula (I), Q^(A) represents any one of the following groups:

[wherein R¹⁵ represents a hydrogen atom, a hydroxyl group, a nitrogroup, a cyano group, a halogen atom, an alkyl group, a hydroxyalkylgroup, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, acarboxyalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, analkoxycarbonylalkyl group, an alkylcarbonyloxy group or a group A³-B-(wherein A³ represents an amino group which may have one or twosubstituents, a saturated or unsaturated 5- or 6-membered cyclichydrocarbon group which may have a substituent or a saturated orunsaturated 5- or 6-membered heterocyclic group which may have asubstituent and B³ represents a single bond, a carbonyl group, analkylene group, a carbonylalkyl group, a carbonylalkyloxy group or analkylenecarbonyloxy group), R¹⁶ and R¹⁷ each independently represents ahydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl grouphaving a hydroxyl group which may be protected or an alkoxyalkyl group,or R¹⁶ or R¹⁷ may be coupled together with R¹⁵ and represent a C₁₋₃alkylene or alkenylene group, R¹⁸ and R¹⁹ each independently representsa hydrogen atom, a hydroxyl group, a halogen atom, a halogenoalkylgroup, an alkyl group, an alkoxyl group, an alkenyl group, an alkynylgroup which may be substituted by an alkylsilyl group as a protectinggroup, a trifluoromethyl group, a cyano group, an amino group, anaminoalkyl group, an alkylaminoalkyl group, an amidino group, ahydroxyamidino group or an alkoxycarbonylamidino group, with the provisothat R¹⁸ and R¹⁹ do not represent a hydrogen atom at the same time), andX¹ and X² each independently represents a methine group or a nitrogenatom].

[wherein X³ represents a nitrogen atom, or a group ═C(R¹⁰⁰)— (whereinR¹⁰⁰ represents a hydrogen atom, a halogen atom, an alkyl group, analkoxycarbonyl group, an aralkyloxycarbonylalkyl group, analkoxycarbonylalkyl group, a nitro group, an amino group which may havea protecting group or an aminoalkyl group which may have, at the aminomoiety thereof, a protecting group), X⁴ represents an oxygen atom, asulfur atom or a group —N(R¹⁰¹)— (wherein R¹⁰¹ means a hydrogen atom, analkyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, analkoxycarbonylalkyl group, an alkylsulfonyl group or an arylsulfonylgroup), X⁵ and X⁸ each independently represents a nitrogen atom or agroup —C(R¹⁰²)— (wherein R¹⁰² represents a hydrogen atom or a halogenatom), X⁶ and X⁷ each independently represents a nitrogen atom or agroup —C(R¹⁰³)— (wherein R¹⁰³ represents a hydrogen atom, a hydroxylgroup, a halogen atom, a halogenoalkyl group, an alkyl group, an alkoxylgroup, an alkenyl group, an alkynyl group which may be substituted by analkylsilyl group as a protecting group, a cyano group, an amino group,an aminoalkyl group, an alkylaminoalkyl group, an amidino group, ahydroxyamidino group or an alkoxycarbonylamidino group)].

[wherein X⁹ and X¹² each independently represents a nitrogen atom or agroup —C(R¹⁰⁴)— (wherein R¹⁰⁴ represents a hydrogen atom or a halogenatom), X¹⁰ and X¹¹ each independently represents a nitrogen atom or agroup —C(R¹⁰⁵)— (wherein R¹⁰⁵ represents a hydrogen atom, a hydroxylgroup, a halogen atom, a halogenoalkyl group, an alkyl group, an alkoxylgroup, an alkenyl group, an alkynyl group which may be substituted by analkylsilyl group as a protecting group, a cyano group, an amino group,an aminoalkyl group, an alkylaminoalkyl group, an amidino group, ahydroxyamidino group or an alkoxycarbonylamidino group, and w and z eachindependently represents an integer of 1 or 2], or salt thereof; or asolvate thereof.
 3. A sulfonyl derivative according to claim 2, whereinin the formula (I), the group:

means the following group:

[in the above formulas, R¹⁶, R¹⁸, R¹⁹, X¹ and X² have the same meaningsas defined above], or salt thereof; or a solvate thereof.
 4. A sulfonylderivative according to claim 2 or 3, wherein R¹⁸ represents a halogenatom or an ethynyl group, or salt thereof; or a solvate thereof.
 5. Asulfonyl derivative according to claim 2, wherein in the formula (I),the group:

means any one of the following groups:

[in the above formulas, R¹⁰¹ and R¹⁰³ have the same meanings as definedabove and R^(103′) represents similar atoms or groups to R¹⁰³], or saltthereof; or a solvate thereof.
 6. A sulfonyl derivative according toclaim 5, wherein either one of R¹⁰³ and R^(103′) represents a halogenatom or an ethynyl group, or salt thereof; or a solvate thereof.
 7. Asulfonyl derivative according to claim 2, wherein in the formula (I),the group:

represents the following group:

[wherein R¹⁰⁵ has the same meaning as defined above and R^(105′)represents similar atoms or groups to R¹⁰⁵], or salt thereof; or asolvate thereof.
 8. A sulfonyl derivative according to claim 7, whereineither one of R¹⁰⁵ or R^(105′) represents a halogen atom or an ethynylgroup, or salt thereof; or a solvate thereof.
 9. A sulfonyl derivativeaccording to any one of claims 1 to 8, wherein Q³ represents the group:

[wherein R³, R⁴, a, b and c have the same meanings as defined above] orsalt thereof; or a solvate thereof.
 10. A sulfonyl derivative accordingto any one of claims 1 to 9, wherein T¹ represents a carbonyl group or agroup —CH(R³)— (wherein R¹³ has the same meaning as defined above). 11.A sulfonyl derivative according to any one of clams 1 to 10, wherein Q¹represents a cyclopentyl group which may have a substituent, cyclohexylgroup which may have a substituent, cyclopentenyl group which may have asubstituent, cyclohexenyl group which may have a substituent, phenylgroup which may have a substituent, pyrrolidinyl group which may have asubstituent, piperidinyl group which may have a substituent, imidazolylgroup which may have a substituent, thiazolyl group which may have asubstituent, thiadiazolyl group which may have a substituent, pyridylgroup which may have a substituent, pyrimidinyl group which may have asubstituent, pyridazinyl group which may have a substituent,thiazolydinyl group which may have a substituent, morpholinyl groupwhich may have a substituent, piperazinyl group which may have asubstituent, thiomorpholinyl group which may have a substituent,pyrrolyl group which may have a substituent, thienyl group which mayhave a substituent, furanyl group which may have a substituent,tetrahydropyrimidinyl group which may have a substituent,tetrahydrofuranyl group which may have a substituent, tetrahydrothienylgroup which may have a substituent, sulforanyl group which may have asubstituent, imidazolinyl group which may have a substituent,thiazolinyl group which may have a substituent, oxazolyl group which mayhave a substituent, oxadiazinyl group which may have a substituent,triazinyl group which may have a substituent, tetrazinyl group which mayhave a substituent, pyrazinyl group which may have a substituent,pyrazolyl group which may have a substituent, pyrazolinyl group whichmay have a substituent, pyrazolidinyl group which may have asubstituent, thienopyridyl group which may have a substituent,tetrahydrothienopyridyl group which may have a substituent,thiazolopyridyl group which may have a substituent,tetrahydrothiazolopyridyl group which may have a substituent,pyranothiazolyl group which may have a substituent,dihydropyranothiazolyl group which may have a subsituent,thiazolopyridadinyl group which may have a substituent,tetrahydrothiazolopyridadinyl group which may have a substituent,furopyridyl group which may have a substituent, tetrahydrofuropyridylgroup which may have a substituent, oxazolopyridyl group which may havea substituent, and tetrahydrooxazolopyridyl group which may have asubstituent.
 12. A medicament comprising as an effective ingredient asulfonyl derivative or salt thereof, or a solvate thereof as claimed inany one of claims 1 to
 11. 13. An inhibitor for an activated coagulationfactor X which comprises as an effective ingredient a sulfonylderivative or salt thereof, or a solvate thereof as claimed in any oneof claims 1 to
 11. 14. A coagulation suppressor comprising as aneffective ingredient a sulfonyl derivative or salt thereof, or a solvatethereof as claimed in any one of claims 1 to
 11. 15. A preventive and/orremedy for thrombosis or embolism which comprises as an effectiveingredient a sulfonyl derivative or salt thereof, or a solvate thereofas claimed in any one of claims 1 to
 11. 16. A preventive and/or remedyfor cerebral infarction, cerebral embolism, myocardial infarction,pulmonary infarction, pulmonary embolism, Buerger's disease, deep veinthrombosis, disseminated intravascular coagulation syndrome, thrombusformation after valve replacement, reocclusion after revascularization,formation of thrombus upon extracorporeal circulation or coagulationupon blood collection, which comprises as an effective ingredient asulfonyl derivative or salt thereof, or a solvate thereof as claimed inany one of claims 1 to
 11. 17. A pharmaceutical composition comprising asulfonyl derivative or salt thereof, or a solvent thereof as claimed inany one of claims 1 to 11, and a pharmaceutically acceptable carrier.18. Use of a sulfonyl derivative or salt thereof, or a solvent thereofas claimed in any one of claims 1 to 11 as a medicament.
 19. Use of asulfonyl derivative or salt thereof, or a solvent thereof as claimed inany one of claims 1 to 11 as an inhibitor of an activated coagulationfactor X.
 20. Use of a sulfonyl derivative or salt thereof, or a solventthereof as claimed in any one of claims 1 to 11 as a coagulationsuppressor.
 21. Use of a sulfonyl derivative or salt thereof, or asolvent thereof as claimed in any one of claims 1 to 11 as a preventiveor remedy for thrombosis or embolism.
 22. Use of a sulfonyl derivativeor salt thereof, or a solvent thereof as claimed in any one of claims 1to 11 as a preventive and/or remedy for cerebral infarction, cerebralembolism, myocardial infarction, pulmonary infarction, pulmonaryembolism, Buerger's disease, deep vein thrombosis, disseminatedintravascular coagulation syndrome, thrombus formation after valvereplacement, reocclusion after revascularization, formation of thrombusupon extracorporeal circulation or coagulation upon blood collection.23. A method for treating diseases caused by an activated coagulationfactor X, which comprises administering a sulfonyl derivative or saltthereof, or a solvate thereof as claimed in any one of claims 1 to 11.24. A treating method for coagulation inhibition, which comprisesadministering a sulfonyl derivative or salt thereof, or a solvatethereof as claimed in any one of claims 1 to
 11. 25. A treating methodof thrombosis or embolism, which comprises administering a sulfonylderivative or salt thereof, or a solvate thereof as claimed in any oneof claims 1 to
 11. 26. A treating method for cerebral infarction,cerebral embolism, myocardial infarction, pulmonary infarction,pulmonary embolism, Buerger's disease, deep vein thrombosis,disseminated intravascular coagulation syndrome, thrombus formationafter valve replacement, reocclusion after revascularization, formationof thrombus upon extracorporeal circulation or coagulation upon bloodcollection, which comprises administering a sulfonyl derivative or saltthereof, or a solvate thereof as claimed in any one of claims 1 to 11.